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Bakewell C, Ashton JJ, Vadgama B, Beattie RM, Batra A. Prevalence and clinical characteristics of children with coexisting coeliac disease and inflammatory bowel disease. Arch Dis Child 2025:archdischild-2025-328470. [PMID: 40355251 DOI: 10.1136/archdischild-2025-328470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 04/18/2025] [Indexed: 05/14/2025]
Abstract
OBJECTIVE Growing evidence suggests that coeliac disease (CeD) is more common in patients with inflammatory bowel disease (IBD) but diagnostic confusion remains due to overlapping histological and clinical features. Few studies have investigated this relationship in children. We aimed to assess the prevalence of CeD in our paediatric IBD cohort and define the characteristics of IBD when CeD coexists. METHODS We conducted a retrospective study of all patients <18 years old diagnosed with IBD in Southampton Children's Hospital between January 2019 and December 2023. Patients were identified using our IBD database, and data were collected on diagnosis, endoscopy, histopathology, serology, IBD treatment and surgery using electronic patient records. RESULTS 18 of the 479 children with IBD were also diagnosed with CeD (3.75%). 14 underwent duodenal biopsy on gluten, with 13 fulfilling Marsh classification 2-3. Eight children had Crohn's disease, five had ulcerative colitis and five had IBD-unclassified. 16 out of 18 demonstrated colonic disease; 11 out of 18 had pancolitis. There was no significant difference in the rate of biological therapy use between the IBD-CeD and non-coeliac groups (50% vs 68%). No patients with IBD-CeD underwent IBD surgery. CONCLUSIONS 1 in 25 children with IBD had coexisting CeD. Pancolitis was the most prominent IBD phenotype but a diagnosis of CeD was not associated with increased escalation to biological therapy, and no patients required surgery. These findings help to describe the paediatric IBD-coeliac phenotype and demonstrate the importance of considering IBD in children with refractory CeD and screening for CeD in children presenting with IBD.
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Affiliation(s)
- Christopher Bakewell
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - James John Ashton
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
- Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - Bhumita Vadgama
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - R Mark Beattie
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Akshay Batra
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
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2
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Hammermeister A, Gaik M, Dahate P, Glatt S. Structural Snapshots of Human tRNA Modifying Enzymes. J Mol Biol 2025:169106. [PMID: 40210523 DOI: 10.1016/j.jmb.2025.169106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/22/2025] [Indexed: 04/12/2025]
Abstract
Cells use a plethora of specialized enzymes to post-transcriptionally introduce chemical modifications into transfer RNA (tRNA) molecules. These modifications contribute novel chemical properties to the affected nucleotides and are crucial for the tRNA maturation process and for most other aspects of tRNA biology. Whereas, some of the modifications are ubiquitous and the respective modifying enzymes are conserved in all domains of life, other modifications are found only in specific organisms, in specific tRNAs or at specific positions of tRNAs. Despite the fact, that evolution has shaped a tremendous variety of tRNA modifications and the respective modification cascades, the clinical relevance of patient-derived mutations has recently led to an increased interest in the set of human tRNA modifying enzymes. Over decades macromolecular crystallography has immensely contributed to understand the enzymatic function of tRNA modifying enzymes at the molecular level. The advent of high resolution single-particle cryo-EM has recently led to structures of several clinically relevant human tRNA modifying enzymes in complex with tRNAs and a more fundamental understanding of the mechanistic consequences of specific disease-related mutations. Here, we aim to provide a comprehensive summary of the currently available experimentally determined structures of human tRNA modifying enzymes.
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Affiliation(s)
| | - Monika Gaik
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Priyanka Dahate
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Sebastian Glatt
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland; Department for Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
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3
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Lei H, Shawki A, Santos AN, Canale V, Manz S, Crawford MS, Chatterjee P, Spalinger MR, Scharl M, McCole DF. PTPN2 Regulates Iron Handling Protein Expression in Inflammatory Bowel Disease Patients and Prevents Iron Deficiency in Mice. Int J Mol Sci 2025; 26:3356. [PMID: 40244226 PMCID: PMC11989999 DOI: 10.3390/ijms26073356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in regulating iron homeostasis. Proteomic analyses were performed on serum from IBD patients genotyped for the IBD-associated loss-of-function rs1893217 PTPN2 variant. Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) mice were analyzed for iron content, blood parameters, and expression of iron handling proteins. Iron absorption was assessed through radiotracer assays. Serum proteomic analyses revealed that the "iron homeostasis signaling pathway" was the main pathway downregulated in Crohn's disease (CD) patients carrying the PTPN2 risk allele, independent of disease activity. Ptpn2-KO mice showed characteristics of anemia, including reduced hemoglobin concentrations along with serum and tissue iron deficiency and elevated serum hepcidin levels vs. Ptpn2-WT and Het mice. 55Fe absorption via oral gavage was significantly impaired in Ptpn2-KO mice. Correspondingly, Ptpn2-KO mice showed reduced apical membrane expression of the iron transporter DMT1. CD patients with the PTPN2 loss-of-function rs1893217 variant display alterations in serum iron handling proteins. Loss of Ptpn2 in mice caused features of anemia, including iron deficiency associated with reduced apical membrane expression of DMT1. These findings identify an important role for PTPN2 in regulating systemic iron homeostasis.
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Affiliation(s)
- Hillmin Lei
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
| | - Ali Shawki
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
| | - Alina N. Santos
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
| | - Vinicius Canale
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
| | - Salomon Manz
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
- Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Meli’sa S. Crawford
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
| | - Pritha Chatterjee
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
| | - Marianne R. Spalinger
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
- Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Declan F. McCole
- School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; (H.L.)
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Ribeiro NV, Anwar S, Withoff S, Jonkers IH. Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells. Int J Mol Sci 2025; 26:2982. [PMID: 40243612 PMCID: PMC11988521 DOI: 10.3390/ijms26072982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/14/2025] [Accepted: 03/23/2025] [Indexed: 04/18/2025] Open
Abstract
The contribution of genetics to the development of gut-related autoimmune diseases such as celiac disease (CeD) and inflammatory bowel diseases (IBDs) is well-established, especially in immune cells, but pinpointing the significance of genetic variants to other cell types is more elusive. Increasing evidence indicates that intestinal epithelial cells are active players in modulating the immune response, suggesting that genetic variants affecting these cells could change cell behavior during disease. Moreover, fine-mapping genetic variants and causal genes to relevant cell types can help to identify drug targets and develop personalized targeted therapies. In this context, we reviewed the functions of genes in disease-associated loci shared by CeD and IBD that are expressed in epithelial cells and explored their potential impacts.
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Affiliation(s)
| | | | | | - Iris H. Jonkers
- Department of Genetics, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; (N.V.R.); (S.A.); (S.W.)
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Li T, Feng Y, Wang C, Shi T, Huang X, Abuduhadeer M, Abudurexiti A, Zhang M, Gao F. Causal relationships between autoimmune diseases and celiac disease: A Mendelian randomization analysis. Biotechnol Genet Eng Rev 2024; 40:4611-4626. [PMID: 37219596 DOI: 10.1080/02648725.2023.2215039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/14/2023] [Indexed: 05/24/2023]
Abstract
The aim of this study was to investigate the causal relationship between autoimmune disorders and celiac disease (CeD) through Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) significantly associated with 13 autoimmune diseases were extracted from the summary statistics of European genome-wide association studies (GWAS), and their effects were examined by Inverse variance-weighted (IVW) in a large European GWAS on CeD. Finally, reverse MR was performed to investigate the causal effects of CeD on autoimmune traits. Following the application of Bonferroni correction for multiple testing, genetically determined seven autoimmune diseases are causally associated with CeD: Crohn's disease (CD) (OR [95%CI] = 1.156 [1.106 ± 1.208], P = 1.27E-10), primary biliary cholangitis (PBC) (1.229 [1.143 ± 1.321], P = 2.53E-08), primary sclerosing cholangitis (PSC) (1.688 [1.466 ± 1.944], P = 3.56E-13), rheumatoid arthritis (RA) (1.231 [1.154 ± 1.313], P = 2.74E-10), systemic lupus erythematosus (SLE) (1.127 [1.081 ± 1.176], P = 2.59E-08), type 1 diabetes (T1D) (1.41 [1.238 ± 1.606], P = 2.24E-07), and asthma (1.414 [1.137 ± 1.758], P = 1.86E-03). The IVW analysis indicated that CeD increased the risk for seven diseases: CD (1.078 [1.044 ± 1.113], P = 3.71E-06), Graves' disease (GD) (1.251 [1.127 ± 1.387], P = 2.34E-05), PSC (1.304 [1.227 ± 1.386], P = 8.56E-18), psoriasis (PsO) (1.12 [1.062 ± 1.182], P = 3.38E-05), SLE (1.301[1.22 ± 1.388], P = 1.25E-15), T1D (1.3[1.228 ± 1.376], P = 1.57E-19), and asthma (1.045 [1.024 ± 1.067], P = 1.82E-05). The sensitivity analyses deemed the results reliable without pleiotropy. There are positive genetic correlations between various autoimmune diseases and CeD, and the latter also affects the predisposition to multiple autoimmune disorders in the European population.
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Affiliation(s)
- Ting Li
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Chun Wang
- Department of Pathology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Tian Shi
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Xiaoling Huang
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Mireayi Abuduhadeer
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Adilai Abudurexiti
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Mengxia Zhang
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Feng Gao
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Disease, Urumqi, Xinjiang, China
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6
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Bester SM, Linwood R, Kataoka R, Wu WI, Mou TC. Enhancing the apo protein tyrosine phosphatase non-receptor type 2 crystal soaking strategy through inhibitor-accessible binding sites. Acta Crystallogr F Struct Biol Commun 2024; 80:210-219. [PMID: 39177701 PMCID: PMC11376276 DOI: 10.1107/s2053230x24007866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/09/2024] [Indexed: 08/24/2024] Open
Abstract
Protein tyrosine phosphatase non-receptor type 2 (PTPN2) has recently been recognized as a promising target for cancer immunotherapy. Despite extensive structural and functional studies of other protein tyrosine phosphatases, there is limited structural understanding of PTPN2. Currently, there are only five published PTPN2 structures and none are truly unbound due to the presence of a mutation, an inhibitor or a loop (related to crystal packing) in the active site. In this report, a novel crystal packing is revealed that resulted in a true apo PTPN2 crystal structure with an unbound active site, allowing the active site to be observed in a native apo state for the first time. Key residues related to accommodation in the active site became identifiable upon comparison with previously published PTPN2 structures. Structures of PTPN2 in complex with an established PTPN1 active-site inhibitor and an allosteric inhibitor were achieved through soaking experiments using these apo PTPN2 crystals. The increased structural understanding of apo PTPN2 and the ability to soak in inhibitors will aid the development of future PTPN2 inhibitors.
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Affiliation(s)
| | - Rebecca Linwood
- Pfizer Boulder Research and Development, Boulder, CO 80301, USA
| | - Ryoko Kataoka
- Pfizer Boulder Research and Development, Boulder, CO 80301, USA
| | - Wen I Wu
- Pfizer Boulder Research and Development, Boulder, CO 80301, USA
| | - Tung Chung Mou
- Pfizer Boulder Research and Development, Boulder, CO 80301, USA
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7
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Wang X, Almetwali O, Wang J, Wright Z, Patton-Tackett ED, Roy S, Tu L, Song G. Enhanced Risk of Gastroesophageal Reflux Disease and Esophageal Complications in the Ulcerative Colitis Population. J Clin Med 2024; 13:4783. [PMID: 39200925 PMCID: PMC11355171 DOI: 10.3390/jcm13164783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/01/2024] [Accepted: 08/12/2024] [Indexed: 09/02/2024] Open
Abstract
Background: Although heartburn and reflux are frequently reported in ulcerative colitis [UC], the correlation between UC and gastroesophageal reflux disease [GERD], and its complications, esophageal stricture and Barrett's esophagus [BE], is not well understood. This study aims to examine the prevalence and associated risk of GERD and its complications within the UC population. Methods: We analyzed the National Inpatient Sample (NIS) dataset, consisting of 7,159,694 patients, comparing GERD patients with and without UC to those without GERD. We assessed the degree of colonic involvement in UC and the occurrence of esophageal complications. Bivariate analyses were conducted using the chi-squared test or Fisher exact test (two-tailed). Results: A higher prevalence of GERD (23.0% vs. 16.5%) and GERD phenotypes, such as non-erosive reflux disease (NERD) (22.3% vs. 16%) and erosive esophagitis (EE) (1.2% vs. 0.6%), was found in UC patients (p < 0.01), including pancolitis, proctitis, proctosigmoiditis, left-sided colitis, and indetermined UC (with undefined colonic involvement). UC patients were more likely to develop GERD (1.421), NERD (1.407), and EE (1.681) (p < 0.01). A higher prevalence of esophageal stricture (16.9 vs. 11.4 per 10,000 patients) and BE without dysplasia (94.5 vs. 39.3 per 10,000 patients) was found in UC (p < 0.05). The odds of developing BE without dysplasia were higher (1.892) in patients with UC (p < 0.01), including ulcerative pancolitis, proctitis, and indeterminate UC (OR of 1.657, 3.328, and 1.996, respectively) (p < 0.05). Conclusions: Our study demonstrates an increased risk of developing GERD and its complications in UC. This highlights the importance of vigilant monitoring and early intervention to minimize associated GERD-related risks in patients with UC.
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Affiliation(s)
- Xiaoliang Wang
- Gastroenterology, Hepatology & Nutrition, Digestive Disease & Surgery Institute, Cleveland Clinic Main Campus, Cleveland, OH 44195, USA;
- Joan C. Edwards School of Medicine, Marshall University Internal Medicine, Huntington, WV 25701, USA; (O.A.); (J.W.); (Z.W.); (E.D.P.-T.); (S.R.)
| | - Omar Almetwali
- Joan C. Edwards School of Medicine, Marshall University Internal Medicine, Huntington, WV 25701, USA; (O.A.); (J.W.); (Z.W.); (E.D.P.-T.); (S.R.)
| | - Jiayan Wang
- Joan C. Edwards School of Medicine, Marshall University Internal Medicine, Huntington, WV 25701, USA; (O.A.); (J.W.); (Z.W.); (E.D.P.-T.); (S.R.)
| | - Zachary Wright
- Joan C. Edwards School of Medicine, Marshall University Internal Medicine, Huntington, WV 25701, USA; (O.A.); (J.W.); (Z.W.); (E.D.P.-T.); (S.R.)
| | - Eva D. Patton-Tackett
- Joan C. Edwards School of Medicine, Marshall University Internal Medicine, Huntington, WV 25701, USA; (O.A.); (J.W.); (Z.W.); (E.D.P.-T.); (S.R.)
| | - Stephen Roy
- Joan C. Edwards School of Medicine, Marshall University Internal Medicine, Huntington, WV 25701, USA; (O.A.); (J.W.); (Z.W.); (E.D.P.-T.); (S.R.)
| | - Lei Tu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gengqing Song
- Department of Gastroenterology and Hepatology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH 44109, USA
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Guillen-Angel M, Roignant JY. Exploring pseudouridylation: dysregulation in disease and therapeutic potential. Curr Opin Genet Dev 2024; 87:102210. [PMID: 38833893 DOI: 10.1016/j.gde.2024.102210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/03/2024] [Accepted: 05/17/2024] [Indexed: 06/06/2024]
Abstract
Pseudouridine (Ψ), the most abundant RNA modification, plays a role in pre-mRNA splicing, RNA stability, protein translation efficiency, and cellular responses to environmental stress. Dysregulation of pseudouridylation is linked to human diseases. This review explores recent insights into the role of RNA pseudouridylation alterations in human disorders and the therapeutic potential of Ψ. We discuss the impact of the reduction of Ψ levels in ribosomal, messenger, and transfer RNA in RNA processing, protein translation, and consequently its role in neurodevelopmental diseases and cancer. Furthermore, we review the success of N1-methyl-Ψ messenger RNA vaccines against COVID-19 and the development of RNA-guided pseudouridylation enzymes for treating genetic diseases caused by premature stop codons.
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Affiliation(s)
- Maria Guillen-Angel
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland
| | - Jean-Yves Roignant
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128 Mainz, Germany.
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9
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Lin TY, Kleemann L, Jeżowski J, Dobosz D, Rawski M, Indyka P, Ważny G, Mehta R, Chramiec-Głąbik A, Koziej Ł, Ranff T, Fufezan C, Wawro M, Kochan J, Bereta J, Leidel SA, Glatt S. The molecular basis of tRNA selectivity by human pseudouridine synthase 3. Mol Cell 2024; 84:2472-2489.e8. [PMID: 38996458 PMCID: PMC11258540 DOI: 10.1016/j.molcel.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 03/14/2024] [Accepted: 06/13/2024] [Indexed: 07/14/2024]
Abstract
Pseudouridine (Ψ), the isomer of uridine, is ubiquitously found in RNA, including tRNA, rRNA, and mRNA. Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs. However, the molecular mechanisms by which it recognizes its RNA targets and achieves site specificity remain elusive. Here, we determine single-particle cryo-EM structures of PUS3 in its apo form and bound to three tRNAs, showing how the symmetric PUS3 homodimer recognizes tRNAs and positions the target uridine next to its active site. Structure-guided and patient-derived mutations validate our structural findings in complementary biochemical assays. Furthermore, we deleted PUS1 and PUS3 in HEK293 cells and mapped transcriptome-wide Ψ sites by Pseudo-seq. Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no evidence that human PUS3 modifies mRNAs. Our work provides the molecular basis for PUS3-mediated tRNA modification in humans and explains how its tRNA modification activity is linked to intellectual disabilities.
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Affiliation(s)
- Ting-Yu Lin
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland.
| | - Leon Kleemann
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Jakub Jeżowski
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Dominika Dobosz
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Michał Rawski
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, 30-392 Kraków, Poland
| | - Paulina Indyka
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, 30-392 Kraków, Poland
| | - Grzegorz Ważny
- SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, 30-392 Kraków, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Kraków, Poland
| | - Rahul Mehta
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Kraków, Poland
| | | | - Łukasz Koziej
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Tristan Ranff
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany
| | - Christian Fufezan
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany
| | - Mateusz Wawro
- Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Jakub Kochan
- Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Joanna Bereta
- Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Sebastian A Leidel
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
| | - Sebastian Glatt
- Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland.
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10
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Jalan A, Jayasree PJ, Karemore P, Narayan KP, Khandelia P. Decoding the 'Fifth' Nucleotide: Impact of RNA Pseudouridylation on Gene Expression and Human Disease. Mol Biotechnol 2024; 66:1581-1598. [PMID: 37341888 DOI: 10.1007/s12033-023-00792-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 06/08/2023] [Indexed: 06/22/2023]
Abstract
Cellular RNAs, both coding and noncoding are adorned by > 100 chemical modifications, which impact various facets of RNA metabolism and gene expression. Very often derailments in these modifications are associated with a plethora of human diseases. One of the most oldest of such modification is pseudouridylation of RNA, wherein uridine is converted to a pseudouridine (Ψ) via an isomerization reaction. When discovered, Ψ was referred to as the 'fifth nucleotide' and is chemically distinct from uridine and any other known nucleotides. Experimental evidence accumulated over the past six decades, coupled together with the recent technological advances in pseudouridine detection, suggest the presence of pseudouridine on messenger RNA, as well as on diverse classes of non-coding RNA in human cells. RNA pseudouridylation has widespread effects on cellular RNA metabolism and gene expression, primarily via stabilizing RNA conformations and destabilizing interactions with RNA-binding proteins. However, much remains to be understood about the RNA targets and their recognition by the pseudouridylation machinery, the regulation of RNA pseudouridylation, and its crosstalk with other RNA modifications and gene regulatory processes. In this review, we summarize the mechanism and molecular machinery involved in depositing pseudouridine on target RNAs, molecular functions of RNA pseudouridylation, tools to detect pseudouridines, the role of RNA pseudouridylation in human diseases like cancer, and finally, the potential of pseudouridine to serve as a biomarker and as an attractive therapeutic target.
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Affiliation(s)
- Abhishek Jalan
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - P J Jayasree
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - Pragati Karemore
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - Kumar Pranav Narayan
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - Piyush Khandelia
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India.
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11
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Skoracka K, Hryhorowicz S, Tovoli F, Raiteri A, Rychter AM, Słomski R, Dobrowolska A, Granito A, Krela-Kaźmierczak I. From an understanding of etiopathogenesis to novel therapies-what is new in the treatment of celiac disease? Front Pharmacol 2024; 15:1378172. [PMID: 38698821 PMCID: PMC11063403 DOI: 10.3389/fphar.2024.1378172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/02/2024] [Indexed: 05/05/2024] Open
Abstract
Celiac disease, a chronic autoimmune disorder caused by genetic factors and exposure to gluten, is increasingly being recognized and diagnosed in both children and adults. Scientists have been searching for a cure for this disease for many years, but despite the impressive development of knowledge in this field, a gluten-free diet remains the only recommended therapy for all patients. At the same time, the increasing diagnosis of celiac disease in adults, which was considered a childhood disease in the 20th century, has opened a discussion on the etiopathology of the disease, which is proven to be very complex and involves genetic, immunological, nutritional, environmental and gut microbiota-related factors. In this review, we extensively discuss these factors and summarize the knowledge of the proposed state-of-the-art treatments for celiac disease to address the question of whether a better understanding of the etiopathogenesis of celiac disease has opened new directions for therapy.
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Affiliation(s)
- Kinga Skoracka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alberto Raiteri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Anna Maria Rychter
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Iwona Krela-Kaźmierczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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12
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Paremskaia AI, Kogan AA, Murashkina A, Naumova DA, Satish A, Abramov IS, Feoktistova SG, Mityaeva ON, Deviatkin AA, Volchkov PY. Codon-optimization in gene therapy: promises, prospects and challenges. Front Bioeng Biotechnol 2024; 12:1371596. [PMID: 38605988 PMCID: PMC11007035 DOI: 10.3389/fbioe.2024.1371596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/19/2024] [Indexed: 04/13/2024] Open
Abstract
Codon optimization has evolved to enhance protein expression efficiency by exploiting the genetic code's redundancy, allowing for multiple codon options for a single amino acid. Initially observed in E. coli, optimal codon usage correlates with high gene expression, which has propelled applications expanding from basic research to biopharmaceuticals and vaccine development. The method is especially valuable for adjusting immune responses in gene therapies and has the potenial to create tissue-specific therapies. However, challenges persist, such as the risk of unintended effects on protein function and the complexity of evaluating optimization effectiveness. Despite these issues, codon optimization is crucial in advancing gene therapeutics. This study provides a comprehensive review of the current metrics for codon-optimization, and its practical usage in research and clinical applications, in the context of gene therapy.
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Affiliation(s)
- Anastasiia Iu Paremskaia
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Anna A. Kogan
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Anastasiia Murashkina
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Daria A. Naumova
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Anakha Satish
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Ivan S. Abramov
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
- The MCSC named after A. S. Loginov, Moscow, Russia
| | - Sofya G. Feoktistova
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Olga N. Mityaeva
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Andrei A. Deviatkin
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
| | - Pavel Yu Volchkov
- Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow, Russia
- The MCSC named after A. S. Loginov, Moscow, Russia
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13
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O'Brien CL, Summers KM, Martin NM, Carter-Cusack D, Yang Y, Barua R, Dixit OVA, Hume DA, Pavli P. The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility to inflammatory bowel disease. Hum Genet 2024; 143:233-261. [PMID: 38421405 PMCID: PMC11043138 DOI: 10.1007/s00439-024-02642-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/14/2024] [Indexed: 03/02/2024]
Abstract
The differentiation of resident intestinal macrophages from blood monocytes depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). Analysis of genome-wide association studies (GWAS) indicates that dysregulation of macrophage differentiation and response to microorganisms contributes to susceptibility to chronic inflammatory bowel disease (IBD). Here, we analyzed transcriptomic variation in monocyte-derived macrophages (MDM) from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. Transcriptional network analysis of the data revealed no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the temporal response to lipopolysaccharide (LPS). However, the basal or LPS-inducible expression of individual genes varied independently by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) in macrophages was associated with HLA genotype. Correlation analysis indicated the downstream impacts of variation in the immediate early response to LPS. For example, variation in early expression of IL1B was significantly associated with local SNV genotype and with subsequent peak expression of target genes including IL23A, CXCL1, CXCL3, CXCL8 and NLRP3. Similarly, variation in early IFNB1 expression was correlated with subsequent expression of IFN target genes. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu is associated with genetic susceptibility to IBD.
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Affiliation(s)
- Claire L O'Brien
- Centre for Research in Therapeutics Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia
| | - Kim M Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Natalia M Martin
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia
| | - Dylan Carter-Cusack
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Yuanhao Yang
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Rasel Barua
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia
| | - Ojas V A Dixit
- Centre for Research in Therapeutics Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
| | - David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
| | - Paul Pavli
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia.
- School of Medicine and Psychology, College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
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14
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Chen JL, Leeder WM, Morais P, Adachi H, Yu YT. Pseudouridylation-mediated gene expression modulation. Biochem J 2024; 481:1-16. [PMID: 38174858 DOI: 10.1042/bcj20230096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/13/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024]
Abstract
RNA-guided pseudouridylation, a widespread post-transcriptional RNA modification, has recently gained recognition for its role in cellular processes such as pre-mRNA splicing and the modulation of premature termination codon (PTC) readthrough. This review provides insights into its mechanisms, functions, and potential therapeutic applications. It examines the mechanisms governing RNA-guided pseudouridylation, emphasizing the roles of guide RNAs and pseudouridine synthases in catalyzing uridine-to-pseudouridine conversion. A key focus is the impact of RNA-guided pseudouridylation of U2 small nuclear RNA on pre-mRNA splicing, encompassing its influence on branch site recognition and spliceosome assembly. Additionally, the review discusses the emerging role of RNA-guided pseudouridylation in regulating PTC readthrough, impacting translation termination and genetic disorders. Finally, it explores the therapeutic potential of pseudouridine modifications, offering insights into potential treatments for genetic diseases and cancer and the development of mRNA vaccine.
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Affiliation(s)
- Jonathan L Chen
- Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester Medical Center, Rochester, NY, U.S.A
| | | | | | - Hironori Adachi
- Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester Medical Center, Rochester, NY, U.S.A
| | - Yi-Tao Yu
- Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester Medical Center, Rochester, NY, U.S.A
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15
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Morrill V, Benke K, Brinton J, Soke GN, Schieve LA, Fields V, Farzadegan H, Holingue C, Newschaffer CJ, Reynolds AM, Daniele Fallin M, Ladd-Acosta C. Genetic liability for gastrointestinal inflammation disorders and association with gastrointestinal symptoms in children with and without autism. Am J Med Genet B Neuropsychiatr Genet 2024; 195:e32952. [PMID: 37455590 PMCID: PMC10792104 DOI: 10.1002/ajmg.b.32952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 06/12/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023]
Abstract
Children with autism spectrum disorder (ASD) have a greater prevalence of gastrointestinal (GI) symptoms than children without ASD. We tested whether polygenic scores for each of three GI disorders (ulcerative colitis, inflammatory bowel disease, and Crohn's disease) were related to GI symptoms in children with and without ASD. Using genotyping data (564 ASD cases and 715 controls) and external genome-wide association study summary statistics, we computed GI polygenic scores for ulcerative colitis (UC-PGS), inflammatory bowel disease (IDB-PGS), and Crohn's disease (CD-PGS). Multivariable logistic regression models, adjusted for genetic ancestry, were used to estimate associations between each GI-PGS and (1) ASD case-control status, and (2) specific GI symptoms in neurotypical children and separately in ASD children. In children without ASD, polygenic scores for ulcerative colitis were significantly associated with experiencing any GI symptom (adjusted odds ratio (aOR) = 1.36, 95% confidence interval (CI) = 1.03-1.81, p = 0.03) and diarrhea specifically (aOR = 5.35, 95% CI = 1.77-26.20, p = 0.01). Among children without ASD, IBD-PGS, and Crohn's PGS were significantly associated with diarrhea (aOR = 3.55, 95% CI = 1.25-12.34, p = 0.02) and loose stools alternating with constipation (aOR = 2.57, 95% CI = 1.13-6.55, p = 0.03), respectively. However, the three PGS were not associated with GI symptoms in the ASD case group. Furthermore, polygenic scores for ulcerative colitis significantly interacted with ASD status on presentation of any GI symptom within a European ancestry subset (aOR = 0.42, 95% CI = 0.19-0.88, p = 0.02). Genetic risk factors for some GI symptoms differ between children with and without ASD. Furthermore, our finding that increased genetic risks for GI inflammatory disorders are associated with GI symptoms in children without ASD informs future work on the early detection of GI disorders.
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Affiliation(s)
- Valerie Morrill
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Kelly Benke
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - John Brinton
- Department of Pediatrics, School of Medicine, University of Colorado and Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Gnakub N. Soke
- Centers for Disease Control and Prevention, Division of Scientific Education and Professional Development, Epidemic Intelligence Service, Atlanta, Georgia, USA
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Laura A. Schieve
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Victoria Fields
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Homayoon Farzadegan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Calliope Holingue
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Craig J. Newschaffer
- AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania, USA
- College of Health and Human Development, Pennsylvania State University, Pennsylvania, USA
| | - Ann M. Reynolds
- Department of Pediatrics, School of Medicine, University of Colorado and Children’s Hospital Colorado, Aurora, Colorado, USA
| | - M. Daniele Fallin
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Christine Ladd-Acosta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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16
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Rodell R, Robalin N, Martinez NM. Why U matters: detection and functions of pseudouridine modifications in mRNAs. Trends Biochem Sci 2024; 49:12-27. [PMID: 38097411 PMCID: PMC10976346 DOI: 10.1016/j.tibs.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 01/07/2024]
Abstract
The uridine modifications pseudouridine (Ψ), dihydrouridine, and 5-methyluridine are present in eukaryotic mRNAs. Many uridine-modifying enzymes are associated with human disease, underscoring the importance of uncovering the functions of uridine modifications in mRNAs. These modified uridines have chemical properties distinct from those of canonical uridines, which impact RNA structure and RNA-protein interactions. Ψ, the most abundant of these uridine modifications, is present across (pre-)mRNAs. Recent work has shown that many Ψs are present at intermediate to high stoichiometries that are likely conducive to function and at locations that are poised to influence pre-/mRNA processing. Technological innovations and mechanistic investigations are unveiling the functions of uridine modifications in pre-mRNA splicing, translation, and mRNA stability, which are discussed in this review.
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Affiliation(s)
- Rebecca Rodell
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Nicolas Robalin
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
| | - Nicole M Martinez
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
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17
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Ballan M, Bovo S, Bertolini F, Schiavo G, Schiavitto M, Negrini R, Fontanesi L. Population genomic structures and signatures of selection define the genetic uniqueness of several fancy and meat rabbit breeds. J Anim Breed Genet 2023; 140:663-678. [PMID: 37435689 DOI: 10.1111/jbg.12818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/25/2023] [Accepted: 07/02/2023] [Indexed: 07/13/2023]
Abstract
Following the recent domestication process of the European rabbit (Oryctolagus cuniculus), many different breeds and lines, distinguished primarily by exterior traits such as coat colour, fur structure and body size and shape, have been constituted. In this study, we genotyped, with a high-density single-nucleotide polymorphism panel, a total of 645 rabbits from 10 fancy breeds (Belgian Hare, Champagne d'Argent, Checkered Giant, Coloured Dwarf, Dwarf Lop, Ermine, Giant Grey, Giant White, Rex and Rhinelander) and three meat breeds (Italian White, Italian Spotted and Italian Silver). ADMIXTURE analysis indicated that breeds with similar phenotypic traits (e.g. coat colour and body size) shared common ancestries. Signatures of selection using two haplotype-based approaches (iHS and XP-EHH), combined with the results obtained with other methods previously reported that we applied to the same breeds, we identified a total of 5079 independent genomic regions with some signatures of selection, covering about 1777 Mb of the rabbit genome. These regions consistently encompassed many genes involved in pigmentation processes (ASIP, EDNRA, EDNRB, KIT, KITLG, MITF, OCA2, TYR and TYRP1), coat structure (LIPH) and body size, including two major genes (LCORL and HMGA2) among many others. This study revealed novel genomic regions under signatures of selection and further demonstrated that population structures and signatures of selection, left into the genome of these rabbit breeds, may contribute to understanding the genetic events that led to their constitution and the complex genetic mechanisms determining the broad phenotypic variability present in these untapped rabbit genetic resources.
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Affiliation(s)
- Mohamad Ballan
- Division of Animal Sciences, Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
| | - Samuele Bovo
- Division of Animal Sciences, Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
| | - Francesca Bertolini
- Division of Animal Sciences, Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
| | - Giuseppina Schiavo
- Division of Animal Sciences, Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
| | - Michele Schiavitto
- Associazione Nazionale Coniglicoltori Italiani (ANCI), Volturara Appula, Italy
| | | | - Luca Fontanesi
- Division of Animal Sciences, Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
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18
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Sudholz H, Delconte RB, Huntington ND. Interleukin-15 cytokine checkpoints in natural killer cell anti-tumor immunity. Curr Opin Immunol 2023; 84:102364. [PMID: 37451129 DOI: 10.1016/j.coi.2023.102364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/08/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023]
Abstract
Over recent years, the use of immune checkpoint inhibitors (ICI) has progressed to first and second-line treatments in several cancer types, transforming patient outcomes. While these treatments target T cell checkpoints, such as PD-1, LAG3 and CTLA-4, their efficacy can be compromised through adaptive resistance whereby tumors acquire mutations in genes regulating neoantigen presentation by MHC-I [93]. ICI-responsive tumor types such as advanced metastatic melanoma typically have a high mutational burden and immune infiltration; however, most patients still do not benefit from ICI monotherapy for a number of reasons [94]. This highlights the need for novel immunotherapy strategies that evoke the immune control of tumor cells with low neoantigen/MHC-I expression, overcome immune suppressive tumor microenvironments and promote tumor inflammation. In this regard, targeting natural killer (NK) cells may offer a solution to some of these bottlenecks.
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Affiliation(s)
- Harrison Sudholz
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Rebecca B Delconte
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA
| | - Nicholas D Huntington
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; oNKo-Innate Pty Ltd, Moonee Ponds, Victoria 3039, Australia.
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19
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Wang Y, Zhang Z, He H, Song J, Cui Y, Chen Y, Zhuang Y, Zhang X, Li M, Zhang X, Zhang MQ, Shi M, Yi C, Wang J. Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells. Haematologica 2023; 108:2677-2689. [PMID: 37165848 PMCID: PMC10542847 DOI: 10.3324/haematol.2022.282211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 05/04/2023] [Indexed: 05/12/2023] Open
Abstract
Aged hematopoietic stem cells (HSC) exhibit compromised reconstitution capacity and differentiation-bias towards myeloid lineage, however, the molecular mechanism behind it remains not fully understood. In this study, we observed that the expression of pseudouridine (Ψ) synthase 10 is increased in aged hematopoietic stem and progenitor cells (HSPC) and enforced protein of Ψ synthase 10 (PUS10) recapitulates the phenotype of aged HSC, which is not achieved by its Ψ synthase activity. Consistently, we observed no difference of transcribed RNA pseudouridylation profile between young and aged HSPC. No significant alteration of hematopoietic homeostasis and HSC function is observed in young Pus10-/- mice, while aged Pus10-/- mice exhibit mild alteration of hematopoietic homeostasis and HSC function. Moreover, we observed that PUS10 is ubiquitinated by E3 ubiquitin ligase CRL4DCAF1 complex and the increase of PUS10 in aged HSPC is due to aging-declined CRL4DCAF1- mediated ubiquitination degradation signaling. Taken together, this study for the first time evaluated the role of PUS10 in HSC aging and function, and provided a novel insight into HSC rejuvenation and its clinical application.
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Affiliation(s)
- Yuqian Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084
| | | | - Hanqing He
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084
| | - Jinghui Song
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093
| | - Yang Cui
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084
| | - Yunan Chen
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing
| | - Yuan Zhuang
- Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing
| | - Xiaoting Zhang
- Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing
| | - Mo Li
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191
| | - Xinxiang Zhang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing
| | - Michael Q Zhang
- School of Medicine, Tsinghua University, Beijing 100084, China; MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist; Department of Automation, Tsinghua University, Beijing 100084, China; Department of Biological Sciences, Center for Systems Biology, the University of Texas, Richardson, TX 75080-3021.
| | - Minglei Shi
- School of Medicine, Tsinghua University, Beijing 100084.
| | - Chengqi Yi
- Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing.
| | - Jianwei Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084.
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20
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Chen W, Song T, Zou F, Xia Y, Xing J, Yu W, Rao T, Zhou X, Li C, Ning J, Zhao S, Ruan Y, Cheng F. Prognostic and immunological roles of IL18RAP in human cancers. Aging (Albany NY) 2023; 15:9059-9085. [PMID: 37698530 PMCID: PMC10522399 DOI: 10.18632/aging.205017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 08/21/2023] [Indexed: 09/13/2023]
Abstract
Across several cancers, IL18 receptor accessory protein (IL18RAP) is abnormally expressed, and this abnormality is related to tumor immunity and heterogeneous clinical outcomes. In this study, based on bioinformatics analysis, we discovered that IL18RAP is related to the human tumor microenvironment and promotes various immune cells infiltration. Additionally, the multiple immunofluorescence staining revealed that with the increased expression of IL18RAP, the number of infiltrated M1 macrophages increased. This finding was confirmed by coculture migration analysis using three human cancer cell lines (MDA-MB-231, U251, and HepG2) with IL18RAP knockdown. We discovered a positive link between IL18RAP and the majority of immunostimulators, immunoinhibitors, major histocompatibility complex (MHC) molecules, chemokines, and chemokine receptor genes using Spearman correlation analysis. Additionally, functional IL18RAP's gene set enrichment analysis (GSEA) revealed that it is related to a variety of immunological processes, such as positive regulation of interferon gamma production and positive regulation of NK cell-mediated immunity. Moreover, we used single-cell RNA sequencing analysis to detect that IL18RAP was mainly expressed in immune cells, and HALLMARK analysis confirmed that the INF-γ gene set expression was upregulated in CD8Tex cells. In addition, in human and mouse cancer cohorts, we found that the level of IL18RAP can predict the immunotherapy response. In short, our study showed that IL18RAP is a new tumor biomarker and may become a potential immunotherapeutic target in cancer.
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Affiliation(s)
- Wu Chen
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Tianbao Song
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Fan Zou
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Yuqi Xia
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Ji Xing
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Weimin Yu
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Ting Rao
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Xiangjun Zhou
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Chenglong Li
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Jinzhuo Ning
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Sheng Zhao
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Yuan Ruan
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
| | - Fan Cheng
- Department of Urology, Hubei International Scientific and Technological Cooperation Base of Immunotherapy, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei, P.R. China
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21
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Kaur H, Kaur G, Ali SA. IL-33's role in the gut immune system: A comprehensive review of its crosstalk and regulation. Life Sci 2023; 327:121868. [PMID: 37330043 DOI: 10.1016/j.lfs.2023.121868] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/02/2023] [Accepted: 06/14/2023] [Indexed: 06/19/2023]
Abstract
The intestinal tract is the largest immune organ in the human body, comprising a complex network of immune cells and epithelial cells that perform a variety of functions such as nutrient absorption, digestion, and waste excretion. Maintenance of homeostasis and effective responses to injury in the colonic epithelium are crucial for maintaining homeostasis between these two cell types. The onset and perpetuation of gut inflammation, characterizing inflammatory bowel diseases (IBD), are triggered by constitutive dysregulation of cytokine production. IL-33 is a newly characterized cytokine that has emerged as a critical modulator of inflammatory disorders. IL-33 is constitutively expressed in the nuclei of different cell types such as endothelial, epithelial, and fibroblast-like cells. Upon tissue damage or pathogen encounter, IL-33 is released as an alarmin and signals through a heterodimer receptor that consists of serum Stimulation-2 (ST2) and IL-1 receptor accessory protein (IL-1RAcP). IL-33 has the ability to induce Th2 cytokine production and enhance both Th1 and Th2, as well as Th17 immune responses. Exogenous administration of IL-33 in mice caused pathological changes in most mucosal tissues such as the lung and the gastrointestinal (GI) tract associated with increased production of type 2 cytokines and chemokines. In vivo and in vitro, primary studies have exhibited that IL-33 can activate Th2 cells, mast cells, or basophils to produce type 2 cytokines such as IL-4, IL-5, and IL-13. Moreover, several novel cell populations, collectively referred to as "type 2 innate lymphoid cells," were identified as being IL-33 responsive and are thought to be important for initiating type 2 immunity. Nevertheless, the underlying mechanisms by which IL-33 promotes type 2 immunity in the GI tract remain to be fully understood. Recently, it has been discovered that IL-33 plays important roles in regulatory immune responses. Highly suppressive ST2 + FoxP3+ Tregs subsets regulated by IL-33 were identified in several tissues, including lymphoid organs, gut, lung, and adipose tissues. This review aims to comprehensively summarize the current knowledge on IL-33's role in the gut immune system, its crosstalk, and regulation. The article will provide insights into the potential applications of IL-33-based therapies in the treatment of gut inflammatory disorders.
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Affiliation(s)
- Harpreet Kaur
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Gurjeet Kaur
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia; Mark Wainwright Analytical Centre, Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052, Australia
| | - Syed Azmal Ali
- Division Proteomics of Stem Cells and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany.
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22
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Mu C, Zhao Q, Zhao Q, Yang L, Pang X, Liu T, Li X, Wang B, Fung SY, Cao H. Multi-omics in Crohn's disease: New insights from inside. Comput Struct Biotechnol J 2023; 21:3054-3072. [PMID: 37273853 PMCID: PMC10238466 DOI: 10.1016/j.csbj.2023.05.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 06/06/2023] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) with complex clinical manifestations such as chronic diarrhea, weight loss and hematochezia. Despite the increasing incidence worldwide, cure of CD remains extremely difficult. The rapid development of high-throughput sequencing technology with integrated-omics analyses in recent years has provided a new means for exploring the pathogenesis, mining the biomarkers and designing targeted personalized therapeutics of CD. Host genomics and epigenomics unveil heredity-related mechanisms of susceptible individuals, while microbiome and metabolomics map host-microbe interactions in CD patients. Proteomics shows great potential in searching for promising biomarkers. Nonetheless, single omics technology cannot holistically connect the mechanisms with heterogeneity of pathological behavior in CD. The rise of multi-omics analysis integrates genetic/epigenetic profiles with protein/microbial metabolite functionality, providing new hope for comprehensive and in-depth exploration of CD. Herein, we emphasized the different omics features and applications of CD and discussed the current research and limitations of multi-omics in CD. This review will update and deepen our understanding of CD from integration of broad omics spectra and will provide new evidence for targeted individualized therapeutics.
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Affiliation(s)
- Chenlu Mu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qianjing Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qing Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Lijiao Yang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiaoqi Pang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiaomeng Li
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Shan-Yu Fung
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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23
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Abdelrahman AH, Ibrahim AA, Eid OM, Hassan M, Eid MM, Nour El Din Abd El Baky AM, Ismail M, Abou-Zekri M, Abd El-Fattah SN. A pilot study on promoter methylation of MTHFR, MALT1 and MAP3K7 genes in pediatric celiac disease. HUMAN GENE 2023; 36:201180. [DOI: 10.1016/j.humgen.2023.201180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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24
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AbdullGaffar B, Farhan R. "Brunner gland inflammation in Crohn's disease and Celiac disease: Overlapping inflammatory patterns suggest a possible link". Ann Diagn Pathol 2023; 64:152133. [PMID: 37019032 DOI: 10.1016/j.anndiagpath.2023.152133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023]
Abstract
Similar to celiac disease, inflammatory bowel disease frequently manifests in the duodenum. Histopathologic studies focused on mucosal alterations with little attention to submucosal Brunner glands. Recently, several studies have demonstrated overlapping features between Crohn's disease and celiac disease suggesting a putative link. However, histopathologic studies evaluating this possible link are limited, and those that are focused on Brunner glands are lacking. The present study aims to explore whether Crohn's disease and celiac disease display shared or overlapping inflammatory changes in Brunner glands. We performed a retrospective review study over 17-years retrieving duodenal biopsy specimens containing Brunner gland lobules in patients with Crohn's disease, celiac disease, and ulcerative colitis. We found 10 out of 126 duodenal biopsies (8 %) in patients with Crohn's disease and 6 out of 134 (4.5 %) duodenal biopsies in patients with celiac disease sharing inflammatory patterns in duodenal Brunner gland lobules. Both diseases showed interstitial intralobular and interlobular mixed chronic inflammation with variable fibrosis. Focally enhanced active inflammation of Brunner gland lobules was more characteristic of Crohn's disease. Intralobular epithelioid granulomas and multinucleated giant cells were specific to Crohn's disease. Ulcerative colitis patients did not show similar features. The interstitial focally enhanced chronic inflammatory pattern was significantly (p < 0.05) associated with both diseases, while the other inflammatory patterns were not (p > 0.05). This overlapping inflammatory pattern in Brunner glands in patients with Crohn's disease and celiac disease is supportive of the previously reported link between the two diseases. Pathologists should pay more attention to Brunner glands when evaluating duodenal biopsies. Further studies are warranted to validate these observations and their relevance in the pathogenesis of autoinflammatory gastrointestinal diseases.
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Affiliation(s)
| | - Rabiah Farhan
- Histology unit, Dubai hospital, United Arab Emirates
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25
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Zhang Q, Fei S, Zhao Y, Liu S, Wu X, Lu L, Chen W. PUS7 promotes the proliferation of colorectal cancer cells by directly stabilizing SIRT1 to activate the Wnt/β-catenin pathway. Mol Carcinog 2023; 62:160-173. [PMID: 36222184 DOI: 10.1002/mc.23473] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 01/25/2023]
Abstract
Pseudouridine synthase 7 (PUS7) may play key roles in cancer development. However, few studies have been conducted in this area. In the present study, we explored the function and potential mechanisms of PUS7 in colorectal cancer (CRC) progression. We found that PUS7 had higher expression in CRC tissues and cell lines. Clinically, high expression of PUS7 was associated with an unfavorable prognosis for CRC patients. Functionally, knockdown of PUS7 suppressed the proliferation of CRC cells in vitro and inhibited tumorigenicity in vivo. Mechanistically, RNA sequencing and coimmunoprecipitation (Co-IP) indicated that PUS7 exhibited oncogenic functions through the interaction of Sirtuin 1 (SIRT1) and activated the Wnt/β-catenin signaling pathway. Thus, our findings suggest that PUS7 promotes the proliferation of CRC cells by directly stabilizing SIRT1 to activate the Wnt/β-catenin pathway.
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Affiliation(s)
- Qi Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Sujuan Fei
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yanchao Zhao
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Shengnan Liu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaoting Wu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lili Lu
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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26
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Kaliora AC. Nutrition in inflammatory bowel diseases; Is there a role? Best Pract Res Clin Gastroenterol 2023; 62-63:101827. [PMID: 37094912 DOI: 10.1016/j.bpg.2023.101827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 04/26/2023]
Abstract
Nutrition is of paramount importance not only for healthy individuals, but all the more for the ones with pathologies interlinked with the diet. In that light, diet, when used accordingly can act in a protective manner in inflammatory bowel diseases. The interplay of diet and IBD is not thoroughly defined, and guidelines are a work in progress. However, significant knowledge has been gained with regard to foods and nutrients that may exacerbate or alleviate the core symptoms. Patients with IBD restrict from their diet a plethora of foods often arbitrary, thus depriving themselves from valuable constituents. Careful navigation into the newfound field of genetic variants and personalization of diet should be employed with avoidance of the Westernized diet, processed foods and additives, and focus on a holistic approach with a balanced diet rich in bioactive compounds in order to improve the quality of life of these patients and address diet-related deficiencies.
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Affiliation(s)
- Andriana C Kaliora
- Human Nutrition and Foods, Department of Dietetics-Nutrition Science, School of Health and Education Sciences, Harokopio University, 70 El. Venizelou Ave., 17676, Athens, Greece.
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27
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Hori H. Transfer RNA Modification Enzymes with a Thiouridine Synthetase, Methyltransferase and Pseudouridine Synthase (THUMP) Domain and the Nucleosides They Produce in tRNA. Genes (Basel) 2023; 14:genes14020382. [PMID: 36833309 PMCID: PMC9957541 DOI: 10.3390/genes14020382] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023] Open
Abstract
The existence of the thiouridine synthetase, methyltransferase and pseudouridine synthase (THUMP) domain was originally predicted by a bioinformatic study. Since the prediction of the THUMP domain more than two decades ago, many tRNA modification enzymes containing the THUMP domain have been identified. According to their enzymatic activity, THUMP-related tRNA modification enzymes can be classified into five types, namely 4-thiouridine synthetase, deaminase, methyltransferase, a partner protein of acetyltransferase and pseudouridine synthase. In this review, I focus on the functions and structures of these tRNA modification enzymes and the modified nucleosides they produce. Biochemical, biophysical and structural studies of tRNA 4-thiouridine synthetase, tRNA methyltransferases and tRNA deaminase have established the concept that the THUMP domain captures the 3'-end of RNA (in the case of tRNA, the CCA-terminus). However, in some cases, this concept is not simply applicable given the modification patterns observed in tRNA. Furthermore, THUMP-related proteins are involved in the maturation of other RNAs as well as tRNA. Moreover, the modified nucleosides, which are produced by the THUMP-related tRNA modification enzymes, are involved in numerous biological phenomena, and the defects of genes for human THUMP-related proteins are implicated in genetic diseases. In this review, these biological phenomena are also introduced.
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Affiliation(s)
- Hiroyuki Hori
- Department of Materials Science and Biotechnology, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
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28
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Yuan S, Kim JH, Xu P, Wang Z. Causal association between celiac disease and inflammatory bowel disease: A two-sample bidirectional Mendelian randomization study. Front Immunol 2023; 13:1057253. [PMID: 36685511 PMCID: PMC9845610 DOI: 10.3389/fimmu.2022.1057253] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/12/2022] [Indexed: 01/06/2023] Open
Abstract
Background An epidemiological link between celiac disease (CeD) and inflammatory bowel disease (IBD) has been well established recently. In this study, Mendelian randomization (MR) analysis was performed employing pooled data of publicly available genome-wide association studies (GWAS) to determine the causal relationship between CeD and IBD, encompassing ulcerative colitis (UC) and Crohn's disease (CD). Methods Dataset of CeD was acquired from GWAS for 12,041 cases and 12,228 controls. A GWAS of more than 86,000 patients and controls was used to identify genetic variations underlying IBD. MR analyses were performed with an inverse-variance-weighted approach, an MR-Egger regression, a weighted-mode approach, a weighted-median method, and sensitivity analyses of MR pleiotropy residual sum and outlie (MR-PRESSO). Results MR demonstrated that genetic predisposition to CeD was linked to a augmented risk of IBD (OR: 1.1408; 95% CI: 1.0614-1.2261; P = 0.0003). In the analysis of the two IBD subtypes, genetic predisposition to CeD was also linked to increased risks of UC (OR: 1.1646; 95% CI: 1.0614-1.2779; P = 0.0012) and CD (OR: 1.1865; 95% CI: 1.0948-1.2859; P = 3.07E-05). Reverse MR analysis results revealed that genetic susceptibility to IBD and CD was correlated with an augmented risk of CeD. However, there was no genetic correlation between UC and CeD. All of the above results were validated with other GWAS databases. Conclusion There is a bidirectional causal relationship of CeD with IBD and CD. However, UC only augments the risk of developing CeD.
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Affiliation(s)
- Shuai Yuan
- Division of Pancreatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Ji Hun Kim
- Division of Pancreatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea,*Correspondence: Ji Hun Kim,
| | - Pai Xu
- Department of Orthopaedic Surgery, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Zhao Wang
- Department of Orthopaedic Surgery, Chungnam National University School of Medicine, Daejeon, Republic of Korea
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29
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González Delgado S, Garza-Veloz I, Trejo-Vazquez F, Martinez-Fierro ML. Interplay between Serotonin, Immune Response, and Intestinal Dysbiosis in Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:ijms232415632. [PMID: 36555276 PMCID: PMC9779345 DOI: 10.3390/ijms232415632] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn's disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with increased risk for the disease. 5-Hydroxytriptamine (5-HT), or serotonin, exerts a wide range of gastrointestinal effects under both normal and pathological conditions. Furthermore, Serotonin Transporter (SERT) coded by Solute Carrier Family 6 Member 4 (SLC6A4) gene (located in the 17q11.1-q12 chromosome), possesses genetic variants, such as Serotonin Transporter Gene Variable Number Tandem Repeat in Intron 2 (STin2-VNTR) and Serotonin-Transporter-linked promoter region (5-HTTLPR), which have an influence over the functionality of SERT in the re-uptake and bioavailability of serotonin. The intestinal microbiota is a crucial actor in normal human gut physiology, exerting effects on serotonin, SERT function, and inflammatory processes. As a consequence of abnormal serotonin signaling and SERT function under these inflammatory processes, the use of selective serotonin re-uptake inhibitors (SSRIs) has been seen to improve disease activity and extraintestinal manifestations, such as depression and anxiety. The aim of this study is to integrate scientific data linking the intestinal microbiota as a regulator of gut serotonin signaling and re-uptake, as well as its role in the pathogenesis of IBD. We performed a narrative review, including a literature search in the PubMed database of both review and original articles (no date restriction), as well as information about the SLC6A4 gene and its genetic variants obtained from the Ensembl website. Scientific evidence from in vitro, in vivo, and clinical trials regarding the use of selective serotonin reuptake inhibitors as an adjuvant therapy in patients with IBD is also discussed. A total of 194 articles were used between reviews, in vivo, in vitro studies, and clinical trials.
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30
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Zhou W, Triadafilopoulos G, Fernandez-Becker N. Hiding in Planus Sight: Localized Ulcerative Jejunitis in a Patient with Celiac Disease. Dig Dis Sci 2022; 67:5434-5438. [PMID: 36125592 DOI: 10.1007/s10620-022-07693-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/18/2022] [Indexed: 01/05/2023]
Affiliation(s)
- Wendy Zhou
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - George Triadafilopoulos
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
| | - Nielsen Fernandez-Becker
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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31
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Kori M, Zamir Y, Yermiyahu SO, Ainbinder I, Daichman S, Pinto GD, Loewenberg Weisband Y, Greenfeld S, Kariv R, Lederman N, Matz E, Shamir R, Dotan I, Turner D. The association of Inflammatory Bowel Disease with Celiac Disease and Celiac Autoimmunity in children and adults: A nationwide study from the epi-IIRN. J Crohns Colitis 2022; 17:700-705. [PMID: 36394548 DOI: 10.1093/ecco-jcc/jjac176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND AND AIMS Given the paucity of population-based data on the association between inflammatory bowel diseases (IBD), celiac disease (CeD) and celiac autoimmunity (CeA) we aimed to study the associations in a nationwide study. METHODS Utilizing health administrative data for all four health maintenance organizations in Israel, covering 98% of the population, we explored the prevalence of CeD in children and adults with IBD versus non-IBD matched controls. CeD was defined by three ICD-9 codes and CeA by positivity for tissue transglutaminase antibodies. RESULTS In total, 34,375 IBD patients (56% Crohn's disease [CD] and 44% ulcerative colitis [UC]) were compared with 93,603 non-IBD controls. Among IBD patients, 319 (0.93%) had CeD versus 294 (0.31%) non-IBD controls (odds ratio [OR]=2.97 [95%CI 2.54-3.48]; p<0.001). CeA was identified in 575 (1.67%) IBD patients vs. 158 (0.17%) controls (OR=10.06 [95%CI 8.43-12], p<0.001). The prevalence of CeD was higher in pediatric-onset IBD (87/5,243 [1.66%]) than adult-onset IBD (232/29,132 [0.79%]; p<0.001). CD patients had a higher prevalence of CeD (229/19,264 [1.19%]) than UC patients (90/15,111 [0.56%]; OR=2.01 [95%CI 1.57-2.56]; p<0.001). The diagnosis of CeD preceded the diagnosis of IBD in 241/319 cases (76%). The time to treatment escalation was shorter in patients with both IBD and CeD than in patients with IBD without CeD (p=0.017). CONCLUSION CeD and CeA are more prevalent in IBD patients, especially in pediatric-onset IBD and in CD. The diagnosis of CeD usually precedes that of IBD. Having CeD is associated with more intensified treatment for IBD.
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Affiliation(s)
- Michal Kori
- Pediatric Gastroenterology, Kaplan Medical Center, Rehovot, Israel.,Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yonatan Zamir
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | - Sami Or Yermiyahu
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | - Inessa Ainbinder
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | | | - Gavriel David Pinto
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | | | - Shira Greenfeld
- Clalit Health Services, Clalit Research Institute, Tel-Aviv, Israel.,Maccabi Health Services, Tel-Aviv, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | | | | | - Eran Matz
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Raanan Shamir
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology, the Hebrew university of Jerusalem
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32
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Begik O, Mattick JS, Novoa EM. Exploring the epitranscriptome by native RNA sequencing. RNA (NEW YORK, N.Y.) 2022; 28:1430-1439. [PMID: 36104106 PMCID: PMC9745831 DOI: 10.1261/rna.079404.122] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Chemical RNA modifications, collectively referred to as the "epitranscriptome," are essential players in fine-tuning gene expression. Our ability to analyze RNA modifications has improved rapidly in recent years, largely due to the advent of high-throughput sequencing methodologies, which typically consist of coupling modification-specific reagents, such as antibodies or enzymes, to next-generation sequencing. Recently, it also became possible to map RNA modifications directly by sequencing native RNAs using nanopore technologies, which has been applied for the detection of a number of RNA modifications, such as N6-methyladenosine (m6A), pseudouridine (Ψ), and inosine (I). However, the signal modulations caused by most RNA modifications are yet to be determined. A global effort is needed to determine the signatures of the full range of RNA modifications to avoid the technical biases that have so far limited our understanding of the epitranscriptome.
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Affiliation(s)
- Oguzhan Begik
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
| | - John S Mattick
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
| | - Eva Maria Novoa
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Barcelona 08002, Spain
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A G, Sun C, Shan Y, Husile H, Bai H. Bidirectional causal link between inflammatory bowel disease and celiac disease: A two-sample mendelian randomization analysis. Front Genet 2022; 13:993492. [PMID: 36204317 PMCID: PMC9530974 DOI: 10.3389/fgene.2022.993492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Observational research has shown a correlation between inflammatory bowel disease (IBD) [comprising ulcerative colitis (UC) and Crohn’s disease (CD)] and celiac disease. However, the relationship between these two diseases remains uncertain. Methods: We utilized two-sample Mendelian randomization (MR) to estimate the bidirectional causal relationships between IBD and celiac disease. This study utilized data on single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWASs). Heterogeneity, pleiotropy, and sensitivity analyses were also performed to evaluate the MR results. Results: There was a significant causal relationship between IBD and CD and celiac disease (e.g., IBD and celiac disease, inverse variance weighting (IVW) odds ratio (OR) = 1.0828, 95% CI = 1.0258–1.1428, p = 0.0039; CD and celiac disease, IVW OR = 1.0807, 95% CI = 1.0227–1.1420, p = 0.0058). However, in the reverse direction, we found only suggestive positive causality between celiac disease and CD (e.g., IVW OR = 1.0366, 95% CI = 1.0031–1.0711, p = 0.0319). No evidence of heterogeneity between genetic variants was found (e.g., IBD vs. celiac disease, MR-Egger Q = 47.4391, p = 0.6159). Horizontal pleiotropy hardly influenced causality (e.g., IBD vs. celiac disease, MR-Egger test: p = 0.4340). Leave-one-out analysis showed that individual SNPs did not influence the general results. Conclusion: Our MR analysis revealed a positive causal link between IBD and celiac disease in the European population. In addition, several recommendations for disease prevention and clinical management have been discussed.
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Affiliation(s)
- Gu A
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Caixia Sun
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuezhan Shan
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Husile Husile
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
| | - Haihua Bai
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
- Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
- *Correspondence: Haihua Bai,
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Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chan A, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LW, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabriel SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Irving P, Iyer V, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S, Kupcinskas J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O'Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, Ponsioen CY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Rice DL, Saavalainen P, Sands B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, et alSazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chan A, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LW, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabriel SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Irving P, Iyer V, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S, Kupcinskas J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O'Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, Ponsioen CY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Rice DL, Saavalainen P, Sands B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, Sheikh SZ, Silverberg MS, Simmons A, Skeiceviciene J, Sokol H, Solomonson M, Somineni H, Sun D, Targan S, Turner D, Uhlig HH, van der Meulen AE, Vermeire S, Verstockt S, Voskuil MD, Winter HS, Young J, Duerr RH, Franke A, Brant SR, Cho J, Weersma RK, Parkes M, Xavier RJ, Rivas MA, Rioux JD, McGovern DPB, Huang H, Anderson CA, Daly MJ. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nat Genet 2022; 54:1275-1283. [PMID: 36038634 PMCID: PMC9700438 DOI: 10.1038/s41588-022-01156-2] [Show More Authors] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/12/2022] [Indexed: 01/18/2023]
Abstract
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
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Affiliation(s)
- Aleksejs Sazonovs
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Christine R Stevens
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | | | - Kai Yuan
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Brandon Avila
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Maria T Abreu
- Crohn's and Colitis Center, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Matthieu Allez
- Hopital Saint-Louis, APHP, Universite de Paris, INSERM U1160, Paris, France
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA
| | - Gil Atzmon
- Department for Human Biology, University of Haifa, Haifa, Israel
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Aris Baras
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Jeffrey C Barrett
- Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Nir Barzilai
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
- The Institute for Aging Research, The Nathan Shock Center of Excellence in the Basic Biology of Aging and the Paul F. Glenn Center for the Biology of Human Aging Research at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA
| | - Laurent Beaugerie
- Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
| | - Ashley Beecham
- John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Alain Bitton
- McGill University and McGill University Health Centre, Montreal, Quebec, Canada
| | - Bernd Bokemeyer
- Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Andrew Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA
| | | | | | - Jacques Cosnes
- Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France
| | - David J Cutler
- Department of Human Genetics, Emory University, Atlanta, GA, USA
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Allan Daly
- Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | | | - Lisa W Datta
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Noor Dawany
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Marcella Devoto
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
- University of Rome Sapienza, Rome, Italy
- IRGB - CNR, Cagliari, Italy
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
| | - Sheila Dodge
- Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Eva Ellinghaus
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Laura Fachal
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | | | | | | | | | - Stacey B Gabriel
- Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Tian Ge
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | | | - Kyle Gettler
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mamta Giri
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Benjamin Glaser
- Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Philippe Goyette
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
| | - Daniel Graham
- Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Eija Hämäläinen
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | | | - Mikko Hiltunen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Marc Hoeppner
- Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Peter Irving
- Department of Gastroenterology, Guys and Saint Thomas Hospital, London, UK
- School of Immunology and Microbial Sciences, Kings College London, London, UK
| | - Vivek Iyer
- Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Chaim Jalas
- Director of Genetic Resources and Services, Center for Rare Jewish Genetic Disorders, Bonei Olam, Brooklyn, NY, USA
| | - Judith Kelsen
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Hamed Khalili
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Barbara S Kirschner
- Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA
| | - Kimmo Kontula
- Department of Medicine, Helsinki University Hospital, and Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | - Jukka T Koskela
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Subra Kugathasan
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Christopher A Lamb
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | | | - Chloé Lévesque
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
| | | | - James D Lewis
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
- Crohn's and Colitis Foundation, New York, NY, USA
| | | | - Britt-Sabina Loescher
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | | | - John Mansfield
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sandra May
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Jacob L McCauley
- John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Emebet Mengesha
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Myriam Mni
- University of Liège, ULG, Liège, Belgium
| | | | | | | | | | - David T Okou
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
- Institut National de Sante Publique (INSP), Abidjan, Côte d'Ivoire
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Harry Ostrer
- Albert Einstein College of Medicine, Bronx, NY, USA
| | - Aarno Palotie
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Jean Paquette
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
| | - Joel Pekow
- Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA
| | - Inga Peter
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marieke J Pierik
- Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | | | - Natalie Prescott
- Department of Medical and Molecular Genetics, Kings College London, London, UK
| | - Ann E Pulver
- School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | | | - Daniel L Rice
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Päivi Saavalainen
- Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Bruce Sands
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - Stefan Schreiber
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - L Philip Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | | | - Philippe Seksik
- Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
| | - Rasha Shawky
- IBD BioResource, NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Shehzad Z Sheikh
- Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - Alison Simmons
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Jurgita Skeiceviciene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Harry Sokol
- Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
| | - Matthew Solomonson
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Hari Somineni
- Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Dylan Sun
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Stephan Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Dan Turner
- Shaare Zedek Medical Center, Jerusalem, Israel
| | - Holm H Uhlig
- Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK
- Department of Pediatrics, John Radcliffe Hospital, Oxford, UK
| | - Andrea E van der Meulen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Séverine Vermeire
- University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Sare Verstockt
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | | | | | | | - Andre Franke
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Steven R Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Crohn's Colitis Center of New Jersey, Department of Medicine, Rutgers Robert Wood Johnson Medical School and Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, New Brunswick and Piscataway, NJ, USA
| | - Judy Cho
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Miles Parkes
- Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Ramnik J Xavier
- Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Kurt Isselbacher Professor of Medicine at Harvard Medical School, Cambridge, MA, USA
- Core Institute Member, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Klarman Cell Observatory, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Immunology Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Microbiome Informatics and Therapeutics at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Manuel A Rivas
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | - John D Rioux
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Medicine, Université de Montréal, Montreal, Canada
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Hailiang Huang
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Carl A Anderson
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
| | - Mark J Daly
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
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Goh XT, Fong SK, Chai HC, Kee BP, Chua KH. The first association study of Protein Tyrosine Phosphatase, Non-Receptor Type 2 (PTPN2) gene polymorphisms in Malaysian patients with Crohn's disease. Gene 2022; 836:146661. [PMID: 35680018 DOI: 10.1016/j.gene.2022.146661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 04/21/2022] [Accepted: 06/03/2022] [Indexed: 11/20/2022]
Abstract
Crohn's disease (CD) is one of the sub-entities of Inflammatory Bowel Disease which causes chronic inflammation in the gastrointestinal tract. The development of CD has shown to have a strong genetic association. Therefore, the present study aimed to investigate the association between genetic polymorphisms in a susceptible locus of CD, the protein tyrosine phosphatase, non-receptor type 2 (PTPN2) gene and the development of CD in Malaysian patients. A total of 137 CD patients and 274 matched healthy controls were recruited in the present study. Genomic DNA was extracted from the venous blood of participants and five targeted single nucleotide polymorphisms (SNPs) in the PTPN2 gene were genotyped using polymerase chain reaction. Associations between the SNPs and CD were determined using Fisher's exact test and odds ratio. Findings showed that all five selected SNPs were not significantly associated with the development of CD in Malaysian patients, which was in contrast to studies among the European populations. Malaysian Chinese with rs487273 heterozygous G/T genotype was found to have a lower occurrence of CD (P-value = 0.0253; OR = 0.4396). Patients with rs2542152 homozygous T genotype were associated with stricturing behaviour (P-value = 0.0302, OR = 2.9944). The rs16939895 A/G genotype was associated with inflammation at the ileum site (P-value = 0.0387, OR = 2.2105)while homozygous G genotype was associated with colonic CD (P-value = 0.0164, OR = 2.3917). Functional studies of these SNPs are needed to evaluate their potential use as a biomarker for disease phenotypes among Asian patients.
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Affiliation(s)
- Xiang Ting Goh
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Suh Kuan Fong
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Hwa Chia Chai
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Boon Pin Kee
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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Chatterjee K, Dutta AK, Goel A, Aaron R, Balakrishnan V, Thomas A, John A, Jaleel R, David D, Kurien RT, Chowdhury SD, Simon EG, Joseph AJ, Premkumar P, Pulimood AB. Common polymorphisms of protein tyrosine phosphate non-receptor type 2 gene are not associated with risk of Crohn’s disease in Indian. World J Gastrointest Pathophysiol 2022; 13:114-123. [PMID: 36161231 PMCID: PMC9350595 DOI: 10.4291/wjgp.v13.i4.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/18/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple genetic risk factors for Crohn’s disease (CD) have been identified. However, these observations are not consistent across different populations. The protein tyrosine phosphate non-receptor type 2 (PTPN2) gene plays a role in various aspects of host defense including epithelial barrier function, autophagy, and innate and adaptive immune response. Two common polymorphisms in the PTPN2 gene (rs2542151 and rs7234029) have been associated with risk of CD in Western countries.
AIM To evaluate the association of PTPN2 gene polymorphisms with risk of CD in Indian population.
METHODS We conducted a prospective case-control study. Patients with CD were recruited, and their clinical and investigation details were noted. Controls were patients without organic gastrointestinal disease or other comorbid illnesses. Two common polymorphisms in the PTPN2 gene (rs2542151 and rs7234029) were assessed. DNA was extracted from peripheral blood samples of cases and controls and target DNA was amplified using specific sets of primers. The amplified fragments were digested with restriction enzymes and the presence of polymorphism was detected by restriction fragment length polymorphism. The frequency of alleles was determined. The frequencies of genotypes and alleles were compared between cases and controls to look for significant differences.
RESULTS A total of 108 patients with CD (mean age 37.5 ± 12.7 years, females 42.6%) and 100 controls (mean age 39.9 ± 13.5 years, females 37%) were recruited. For the single nucleotide polymorphism (SNP) rs7234029, the overall frequency of G variant genotype (AG or GG) was noted to be significantly lower in the cases compared to controls (35.2% vs 50%, P = 0.05). For the SNP rs2542151, the overall frequency of G variant genotype (GT or GG) was noted to be similar in cases compared to controls (43.6% vs 47%, P = 0.73). There were no significant differences in minor allele (G) frequency for both polymorphisms between the cases and controls. Both the SNPs had no significant association with age of onset of illness, gender, disease location, disease behaviour, perianal disease, or extraintestinal manifestations of CD.
CONCLUSION Unlike observation form the West, polymorphisms in the PTPN2 gene (rs7234029 and rs2542151) are not associated with an increased risk of developing CD in Indian patients.
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Affiliation(s)
- Kaushik Chatterjee
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Amit Kumar Dutta
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ashish Goel
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Rekha Aaron
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Vijayalekshmi Balakrishnan
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ajith Thomas
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Anoop John
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Rajeeb Jaleel
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Deepu David
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Reuben Thomas Kurien
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - SD Chowdhury
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ebby George Simon
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - AJ Joseph
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Prasanna Premkumar
- Departments of Biostatistics, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Anna B Pulimood
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
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Niu Y, Zheng Y, Zhu H, Zhao H, Nie K, Wang X, Sun L, Song CP. The Arabidopsis Mitochondrial Pseudouridine Synthase Homolog FCS1 Plays Critical Roles in Plant Development. PLANT & CELL PHYSIOLOGY 2022; 63:955-966. [PMID: 35560171 DOI: 10.1093/pcp/pcac060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/16/2022] [Accepted: 05/13/2022] [Indexed: 06/15/2023]
Abstract
As the most abundant RNA modification, pseudouridylation has been shown to play critical roles in Escherichia coli, yeast and humans. However, its function in plants is still unclear. Here, we characterized leaf curly and small 1 (FCS1), which encodes a pseudouridine synthase in Arabidopsis. fcs1 mutants exhibited severe defects in plant growth, such as delayed development and reduced fertility, and were significantly smaller than the wild type at different developmental stages. FCS1 protein is localized in the mitochondrion. The absence of FCS1 significantly reduces pseudouridylation of mitochondrial 26S ribosomal RNA (rRNA) at the U1692 site, which sits in the peptidyl transferase center. This affection of mitochondrial 26S rRNA may lead to the disruption of mitochondrial translation in the fcs1-1 mutant, causing high accumulation of transcripts but low production of proteins. Dysfunctional mitochondria with abnormal structures were also observed in the fcs1-1 mutant. Overall, our results suggest that FCS1-mediated pseudouridylation of mitochondrial 26S rRNA is required for mitochondrial translation, which is critical for maintaining mitochondrial function and plant development.
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Affiliation(s)
- Yanli Niu
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Yuan Zheng
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Huijie Zhu
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Hongyun Zhao
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Kaili Nie
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Xiaopei Wang
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Lirong Sun
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
| | - Chun-Peng Song
- State Key Laboratory of Crop Stress Adaptation and Improvement, School of life Sciences, Henan University, Kaifeng 475001, China
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38
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Akiyama S, Fukuda S, Steinberg JM, Suzuki H, Tsuchiya K. Characteristics of inflammatory bowel diseases in patients with concurrent immune-mediated inflammatory diseases. World J Gastroenterol 2022; 28:2843-2853. [PMID: 35978883 PMCID: PMC9280738 DOI: 10.3748/wjg.v28.i25.2843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/10/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are more likely to have concurrent immune-mediated inflammatory diseases (IMIDs) than those without IBD. IMIDs have been observed to alter the phenotype and outcomes of IBD in recent studies. Several studies have found that IBD patients with concurrent IMIDs may have more extensive or severe disease phenotypes, and are considered to be at increased risk of requiring biologics and IBD-related surgeries, suggesting that having multiple IMIDs is a poor prognostic factor for IBD. Furthermore, IBD patients with primary sclerosing cholangitis and Takayasu arteritis are reported to have unique endoscopic phenotypes, suggesting concurrent IMIDs can influence IBD phenotype with specific intestinal inflammatory distributions. In this review, we discuss the pathogenesis, disease phenotypes, and clinical outcomes in IBD patients with concomitant IMIDs.
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Affiliation(s)
- Shintaro Akiyama
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Soma Fukuda
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Joshua M Steinberg
- Inflammatory Bowel Disease, Gastroenterology of the Rockies, Denver, CO 80218, United States
| | - Hideo Suzuki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
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39
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Wang X, Liu Y. Offense and Defense in Granulomatous Inflammation Disease. Front Cell Infect Microbiol 2022; 12:797749. [PMID: 35846773 PMCID: PMC9277142 DOI: 10.3389/fcimb.2022.797749] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Granulomatous inflammation (GI) diseases are a group of chronic inflammation disorders characterized by focal collections of multinucleated giant cells, epithelioid cells and macrophages, with or without necrosis. GI diseases are closely related to microbes, especially virulent intracellular bacterial infections are important factors in the progression of these diseases. They employ a range of strategies to survive the stresses imposed upon them and persist in host cells, becoming the initiator of the fighting. Microbe-host communication is essential to maintain functions of a healthy host, so defense capacity of hosts is another influence factor, which is thought to combine to determine the result of the fighting. With the development of gene research technology, many human genetic loci were identified to be involved in GI diseases susceptibility, providing more insights into and knowledge about GI diseases. The current review aims to provide an update on the most recent progress in the identification and characterization of bacteria in GI diseases in a variety of organ systems and clinical conditions, and examine the invasion and escape mechanisms of pathogens that have been demonstrated in previous studies, we also review the existing data on the predictive factors of the host, mainly on genetic findings. These strategies may improve our understanding of the mechanisms underlying GI diseases, and open new avenues for the study of the associated conditions in the future.
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Affiliation(s)
- Xinwen Wang
- Shaanxi Clinical Research Center for Oral Diseases, National Clinical Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Department of Oral Medicine, School of Stomatology, The Fourth Military Medical University, Xi’an, China
| | - Yuan Liu
- Shaanxi International Joint Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Department of Histology and Pathology, School of Stomatology, The Fourth Military Medical University, Xi’an, China
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40
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Li X, Li K, Guo W, Wen Y, Meng C, Wu B. Structure Characterization of Escherichia coli Pseudouridine Kinase PsuK. Front Microbiol 2022; 13:926099. [PMID: 35783380 PMCID: PMC9247573 DOI: 10.3389/fmicb.2022.926099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022] Open
Abstract
Pseudouridine (Ψ) is one of the most abundant RNA modifications in cellular RNAs that post-transcriptionally impact many aspects of RNA. However, the metabolic fate of modified RNA nucleotides has long been a question. A pseudouridine kinase (PsuK) and a pseudouridine monophosphate glycosylase (PsuG) in Escherichia coli were first characterized as involved in pseudouridine degradation by catalyzing the phosphorylation of pseudouridine to pseudouridine 5′-phosphate (ΨMP) and further hydrolyzing 5′-ΨMP to produce uracil and ribose 5′-phosphate. Recently, their homolog proteins in eukaryotes were also identified, which were named PUKI and PUMY in Arabidopsis. Here, we solved the crystal structures of apo-EcPsuK and its binary complex with Ψ or N1-methyl-pseudouridine (m1Ψ). The structure of EcPsuK showed a homodimer conformation assembled by its β-thumb region. EcPsuK has an appropriate binding site with a series of hydrophilic and hydrophobic interactions for Ψ. Moreover, our complex structure of EcPsuK-m1Ψ suggested the binding pocket has an appropriate capacity for m1Ψ. We also identified the monovalent ion-binding site and potential ATP-binding site. Our studies improved the understanding of the mechanism of Ψ turnover.
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Affiliation(s)
- Xiaojia Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kangjie Li
- Department of Biopharmaceutical Technology, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Wenting Guo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan Wen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chunyan Meng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Baixing Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Baixing Wu,
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41
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Pantic N, Pantic I, Jevtic D, Mogulla V, Oluic S, Durdevic M, Nordin T, Jecmenica M, Milovanovic T, Gavrancic T, Dumic I. Celiac Disease and Thrombotic Events: Systematic Review of Published Cases. Nutrients 2022; 14:2162. [PMID: 35631302 PMCID: PMC9144428 DOI: 10.3390/nu14102162] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023] Open
Abstract
Extraintestinal manifestations of celiac disease (CD) should be considered, even in patients without typical intestinal symptoms. The aim of our study is to examine the literature regarding the occurrence of thrombotic events in CD, and to synthesize the data from case reports and case series. A systematic review of the literature was conducted by searching the Pub-Med/MEDLINE database, from the date of database inception to January 2022, to identify published cases and case series on this topic, in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 55 cases were included in the study. The majority of patients were previously healthy individuals, with no comorbidities. In less than one-third of the cases (30.91%), the diagnosis of CD was established before the onset of thrombosis, while in the remaining cases (34.54%), thrombosis preceded the diagnosis or was diagnosed concomitantly with CD. The most common sites for thrombosis occurrence were hepatic veins (30.91%), while thrombosis of cerebral blood vessels, deep venous thrombosis of lower extremities, and pulmonary thromboembolism were less frequent. Thrombosis was most commonly isolated to one site only (78.18%). In 69.09% of cases (n = 38), some form of anticoagulation, along with a gluten-free diet, was initiated.
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Affiliation(s)
- Nikola Pantic
- Clinic of Hematology, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
| | - Ivana Pantic
- Clinic of Gastroenterology and Hepatology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (I.P.); (T.M.)
| | - Dorde Jevtic
- Elmhurst Hospital Center, Department of Internal Medicine, Elmhurst, NY 11373, USA;
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Vanajakshi Mogulla
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; (V.M.); (T.N.)
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54703, USA
| | - Stevan Oluic
- Department of Internal Medicine, Loyola University Medical Center, Maywood, IL 60153, USA;
| | - Momcilo Durdevic
- Department of Hospital Medicine, Advocate Aurora Health, Green Bay, WI 54311, USA;
| | - Terri Nordin
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; (V.M.); (T.N.)
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54703, USA
| | | | - Tamara Milovanovic
- Clinic of Gastroenterology and Hepatology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (I.P.); (T.M.)
| | - Tatjana Gavrancic
- Department of Hospital Medicine, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Igor Dumic
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; (V.M.); (T.N.)
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54703, USA
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42
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Kociszewska D, Vlajkovic SM. The Association of Inflammatory Gut Diseases with Neuroinflammatory and Auditory Disorders. Front Biosci (Elite Ed) 2022; 14:8. [PMID: 35730449 DOI: 10.31083/j.fbe1402008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/11/2022] [Accepted: 02/24/2022] [Indexed: 11/06/2022]
Abstract
Disorders such as inflammatory bowel disease (IBD) and celiac disease (CeD) result in intestinal hyperpermeability or 'leaky' gut. The increased permeability of the intestinal barrier allows microbial metabolites, toxins, and pathogens to infiltrate the bloodstream and extraintestinal tissues, causing systemic inflammation. Despite differences in aetiology and pathophysiology, IBD and CeD share several extraintestinal manifestations such as neuroinflammation, neurological and psychiatric manifestations, and sensorineural hearing loss (SNHL). This narrative review focuses on the association between intestinal hyperpermeability with the brain and inner ear diseases. We postulate that the microbial metabolites and pathogens released from the gut increase the permeability of natural barriers, such as the blood-brain barrier (BBB) and blood-labyrinth barrier (BLB). The barrier breakdown allows the spreading of inflammatory processes to the brain and inner ear, leading to disease.
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Affiliation(s)
- Dagmara Kociszewska
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
| | - Srdjan M Vlajkovic
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
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43
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Alkhayyat M, Abureesh M, Almomani A, Abou Saleh M, Zmaili M, El Ouali S, Mansoor E, Rubio-Tapia A, Regueiro M. Patients With Inflammatory Bowel Disease on Treatment Have Lower Rates of Celiac Disease. Inflamm Bowel Dis 2022; 28:385-392. [PMID: 34002219 DOI: 10.1093/ibd/izab084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND The association between celiac disease and inflammatory bowel disease (IBD) has been studied; however, the impact of IBD therapy on celiac disease is not known. Using a large database, we sought to describe the association of celiac disease and IBD and the impact of IBD treatment. METHODS We queried a large multicenter database (Explorys Inc.), an electronic health record data aggregate from 26 American health care systems. We identified a cohort of patients with celiac disease and IBD between 1999 and 2020 and conducted a statistical analysis using a multivariate model. RESULTS Of the 72,965,940 individuals in the database, 133,400 had celiac disease (0.18%), 191,570 (0.26%) had ulcerative colitis (UC), and 230,670 (0.32%) had Crohn disease (CD). Patients with IBD were more likely to have a diagnosis of celiac disease (odds ratio [OR], 13.680), with a greater association with CD. Treated patients with UC and with CD, respectively, had a lower risk association with celiac disease compared to those not undergoing IBD treatment, specifically corticosteroids (OR, 0.407 and 0.585), 5-aminosalicylates (OR, 0.124 and 0.127), immunomodulators (OR, 0.385 and 0.425), and anti-tumor necrosis factor drugs (OR, 0.215 and 0.242). There was no lower risk association in the vedolizumab group, but there was a higher risk association among the ustekinumab group. CONCLUSIONS In this large dataset, we showed a bidirectional association between celiac disease and IBD that was stronger with CD. Patients with IBD treated using corticosteroids, 5-aminosalicylates, immunomodulators, or anti-tumor necrosis factor drugs had a lower association with celiac disease. Additional studies are required to determine the underlying mechanisms for IBD therapy-related modification of celiac disease incidence.
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Affiliation(s)
- Motasem Alkhayyat
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Mohammad Abureesh
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, New York, USA
| | - Ashraf Almomani
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Mohannad Abou Saleh
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Mohammad Zmaili
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Sara El Ouali
- Department of Gastroenterology, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, United Arab Emirates
| | - Emad Mansoor
- Department of Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Alberto Rubio-Tapia
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Miguel Regueiro
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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44
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Martinez NM, Su A, Burns MC, Nussbacher JK, Schaening C, Sathe S, Yeo GW, Gilbert WV. Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing. Mol Cell 2022; 82:645-659.e9. [PMID: 35051350 PMCID: PMC8859966 DOI: 10.1016/j.molcel.2021.12.023] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/04/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
Pseudouridine is a modified nucleotide that is prevalent in human mRNAs and is dynamically regulated. Here, we investigate when in their life cycle mRNAs become pseudouridylated to illuminate the potential regulatory functions of endogenous mRNA pseudouridylation. Using single-nucleotide resolution pseudouridine profiling on chromatin-associated RNA from human cells, we identified pseudouridines in nascent pre-mRNA at locations associated with alternatively spliced regions, enriched near splice sites, and overlapping hundreds of binding sites for RNA-binding proteins. In vitro splicing assays establish a direct effect of individual endogenous pre-mRNA pseudouridines on splicing efficiency. We validate hundreds of pre-mRNA sites as direct targets of distinct pseudouridine synthases and show that PUS1, PUS7, and RPUSD4-three pre-mRNA-modifying pseudouridine synthases with tissue-specific expression-control widespread changes in alternative pre-mRNA splicing and 3' end processing. Our results establish a vast potential for cotranscriptional pre-mRNA pseudouridylation to regulate human gene expression via alternative pre-mRNA processing.
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Affiliation(s)
- Nicole M Martinez
- Yale School of Medicine, Department of Molecular Biophysics & Biochemistry, New Haven, CT 06520, USA
| | - Amanda Su
- Yale School of Medicine, Department of Molecular Biophysics & Biochemistry, New Haven, CT 06520, USA
| | - Margaret C Burns
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Julia K Nussbacher
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Cassandra Schaening
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Shashank Sathe
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
| | - Wendy V Gilbert
- Yale School of Medicine, Department of Molecular Biophysics & Biochemistry, New Haven, CT 06520, USA.
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45
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Del Rosario RCH, Poschmann J, Lim C, Cheng CY, Kumar P, Riou C, Ong ST, Gerges S, Hajan HS, Kumar D, Marzuki M, Lu X, Lee A, Wijaya GC, Rayan NA, Zhuang Z, Du Bruyn E, Chee CBE, Lee B, Lum J, Zolezzi F, Poidinger M, Rotzschke O, Khor CC, Wilkinson RJ, Wang YT, Chandy GK, De Libero G, Singhal A, Prabhakar S. Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection. Nat Microbiol 2022; 7:312-326. [PMID: 35102304 PMCID: PMC9439955 DOI: 10.1038/s41564-021-01049-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/14/2021] [Indexed: 12/23/2022]
Abstract
Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.
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Affiliation(s)
- Ricardo C H Del Rosario
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Jeremie Poschmann
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Inserm, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, ITUN, Nantes, France
| | - Carey Lim
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore
| | | | - Pavanish Kumar
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Catherine Riou
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Seow Theng Ong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Sherif Gerges
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Hajira Shreen Hajan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Dilip Kumar
- Inserm, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, ITUN, Nantes, France
| | - Mardiana Marzuki
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore
| | - Xiaohua Lu
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Andrea Lee
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore
| | - Giovani Claresta Wijaya
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Nirmala Arul Rayan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Zhong Zhuang
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Elsa Du Bruyn
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | | | - Bernett Lee
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Josephine Lum
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | | | | | - Olaf Rotzschke
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Robert J Wilkinson
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Infectious Disease, Imperial College, London, UK
- The Francis Crick Institute, London, UK
| | - Yee T Wang
- Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore, Singapore
| | - George K Chandy
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Gennaro De Libero
- Singapore Immunology Network, A*STAR, Singapore, Singapore
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Amit Singhal
- Singapore Immunology Network, A*STAR, Singapore, Singapore.
- A*STAR Infectious Diseases Labs, A*STAR, Singapore, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
| | - Shyam Prabhakar
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
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46
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Trovato E, Rubegni P, Cinotti E. The Immunogenetics of Psoriasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:105-117. [DOI: 10.1007/978-3-030-92616-8_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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47
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Li Y, Xiao FL, Cheng H, Liang B, Zhou FS, Li P, Zheng XD, Sun LD, Yang S, Zhang XJ. A Common Variant at 11q23.3 Is Associated with Susceptibility to Atopic Dermatitis in the Han Chinese Population. Genet Test Mol Biomarkers 2021; 25:638-645. [PMID: 34609929 DOI: 10.1089/gtmb.2020.0335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Genome-wide association studies (GWASs) have identified many genetic variants that are risk factors for numerous immune-mediated diseases. In particular, different immune-mediated diseases have been found to share the same susceptibility loci. Therefore, exploring the genetic overlap between atopic dermatitis (AD) and other immune-mediated diseases in more detail may help identify additional shared susceptibility loci among common immune-mediated diseases. Recent evidence suggests that the 11q23.3 locus is a susceptibility locus shared among multiple immune-mediated diseases. Objective: This study was designed to investigated whether SNPs at the chromosome 11q23.3 locus are associated with AD in the Han Chinese population. Methods: In total, 16 SNPs within the 11q23.3 locus were genotyped using TaqMan assays for 1,012 AD cases and 1,362 controls. From these SNPs, we selected rs638893 with an association values of p < 5 × 10-2 for AD for further analysis in an independent replication study using the Sequenom MassARRAY system to genotype an additional (consisting of 1,288 cases and 1,380 controls). The combined analyses were performed in two stages using a meta-analytical method. Results: We identified a common variant at 11q23.3 (rs638893), that was significantly associated (p = 1.58 × 10-3, OR = 1.22) with AD. The genotype-based association analysis revealed that the recessive model provided the best fit for rs638893. Conclusion: Our study identified a variant on chromosome 11q23.3 that likely confers susceptibility to AD, thereby advancing our understanding of the genetic basis of this disease.
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Affiliation(s)
- Yang Li
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Feng-Li Xiao
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Hui Cheng
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Bo Liang
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Fu-Sheng Zhou
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Pan Li
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Xiao-Dong Zheng
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Liang-Dan Sun
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Sen Yang
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
| | - Xue-Jun Zhang
- Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China
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48
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Lin TY, Mehta R, Glatt S. Pseudouridines in RNAs: switching atoms means shifting paradigms. FEBS Lett 2021; 595:2310-2322. [PMID: 34468991 PMCID: PMC9290505 DOI: 10.1002/1873-3468.14188] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/18/2021] [Accepted: 08/22/2021] [Indexed: 01/21/2023]
Abstract
The structure, stability, and function of various coding and noncoding RNAs are influenced by chemical modifications. Pseudouridine (Ψ) is one of the most abundant post‐transcriptional RNA base modifications and has been detected at individual positions in tRNAs, rRNAs, mRNAs, and snRNAs, which are referred to as Ψ‐sites. By allowing formation of additional bonds with neighboring atoms, Ψ strengthens RNA–RNA and RNA–protein interactions. Although many aspects of the underlying modification reactions remain unclear, the advent of new transcriptome‐wide methods to quantitatively detect Ψ‐sites has recently changed our perception of the functional roles and importance of Ψ. For instance, it is now clear that the occurrence of Ψs appears to be directly linked to the lifetime and the translation efficiency of a given mRNA molecule. Furthermore, the administration of Ψ‐containing RNAs reduces innate immune responses, which appears strikingly advantageous for the development of generations of mRNA‐based vaccines. In this review, we aim to comprehensively summarize recent discoveries that highlight the impact of Ψ on various types of RNAs and outline possible novel biomedical applications of Ψ.
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Affiliation(s)
- Ting-Yu Lin
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Rahul Mehta
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Sebastian Glatt
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
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49
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Awany D, Allali I, Chimusa ER. Dissecting genome-wide studies for microbiome-related metabolic diseases. Hum Mol Genet 2021; 29:R73-R80. [PMID: 32478833 DOI: 10.1093/hmg/ddaa105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 05/14/2020] [Accepted: 05/29/2020] [Indexed: 12/14/2022] Open
Abstract
Despite the meteoric rise in genome-wide association studies for metabolic diseases (MetD) over the last few years, our understanding of the pathogenesis of these diseases is still far from complete. Recent developments have established that MetD arises from complex interactions between host genetics, the gut microbiome and the environment. However, our knowledge of the genetic and microbiome components involved and the underlying molecular mechanisms remains limited. Here, we review and summarize recent studies investigating the genetic and microbiome basis of MetD. Then, given the critical importance of study-individual's ancestry in these studies, we leverage 4932 whole-genome sequence samples from 18 worldwide ethnic groups to examine genetic diversity in currently reported variants associated with MetD. The analyses show marked differences in gene-specific proportion of pathogenic single-nucleotide polymorphisms (SNPs) and gene-specific SNPs MAFs across ethnic groups, highlighting the importance of population- and ethnic-specific investigations in pinpointing the causative factors for MetD. We conclude with a discussion of research areas where further investigation on interactions between host genetics, microbiome and the environment is needed.
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Affiliation(s)
- Denis Awany
- Division of Human Genetics, Department of Pathology, University of Cape Town, Observatory 7925, Cape Town, South Africa
| | - Imane Allali
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University, Agdal Rabat, B.P, 8007 N.U, Morocco
| | - Emile R Chimusa
- Division of Human Genetics, Department of Pathology, University of Cape Town, Observatory 7925, Cape Town, South Africa.,Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, Cape Town, South Africa
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50
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Song D, Guo M, Xu S, Song X, Bai B, Li Z, Chen J, An Y, Nie Y, Wu K, Wang S, Zhao Q. HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:170. [PMID: 33990203 PMCID: PMC8120699 DOI: 10.1186/s13046-021-01951-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/15/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND Pseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms. METHODS We conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry. RESULTS Overexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis. CONCLUSIONS The HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.
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Affiliation(s)
- Dan Song
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Ming Guo
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Shuai Xu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Xiaotian Song
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Bin Bai
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Zhengyan Li
- Department of General Surgery, Center for Minimally Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gao Tan Yan Road, Chongqing, 400038, China
| | - Jie Chen
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Yanxin An
- Department of General Surgery, the First Affiliated Hospital of Xi 'an Medical University, No. 48 Fenghao West Road, Lianhu District, Xi'an, 710077, Shaanxi Province, China
| | - Yongzhan Nie
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Kaichun Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China
| | - Shiqi Wang
- Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Qingchuan Zhao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China.
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