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1
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Buecking J, An Y, Bi W, Hinderhofer K, Theiß S, Slavotinek A, Schaaf CP. A Case of Prader-Willi Syndrome With a Deletion Including MAGEL2, NDN, and MKRN3, but Excluding SNRPN and SNORD116. Am J Med Genet A 2025:e64070. [PMID: 40231584 DOI: 10.1002/ajmg.a.64070] [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: 01/10/2025] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 04/16/2025]
Abstract
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder typically caused by large deletions or imprinting defects on chromosome 15q11.2, encompassing multiple genes. While the contribution of individual genes to the PWS phenotype remains unclear, previous studies suggested that isolated deletions of MAGEL2, NDN, and MKRN3, excluding the SNRPN/SNORD116 locus, were insufficient to cause PWS. Here, we present a case report of a patient with an isolated deletion of MAGEL2, NDN, and MKRN3 who exhibits the full PWS phenotype, including neonatal hypotonia, developmental delay, hyperphagia, obesity, and behavioral issues. We explore the potential mechanisms underlying this case and investigate the potential contribution of the deleted genes to the observed phenotype. This case challenges previous findings and highlights the complexity of genotype-phenotype correlations in PWS. We compare the clinical data of our patient with previous reports and discuss the discrepancy with earlier findings. Our findings underscore the need for further research to fully elucidate the roles of individual genes within the PWS locus and the mechanisms underlying the phenotypic spectrum of this complex disorder.
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Affiliation(s)
- Jannis Buecking
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Yu An
- Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, California, USA
| | - Weimin Bi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA
| | | | - Susanne Theiß
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Anne Slavotinek
- Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, California, USA
- Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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2
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Martínez JB, Arancedo JMÁ, Solari A, Claps A, Castro T, Laiseca JE, Taboas M. Classic Prader-Willi Syndrome Phenotype Caused by an Atypical Deletion in the 15q11 Region Not Involving the SNORD Genes. Clin Genet 2025. [PMID: 40200592 DOI: 10.1111/cge.14750] [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: 11/28/2024] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/10/2025]
Abstract
Prader-Willi syndrome (PWS) is an uncommon genetic disorder caused by the lack of expression of a cluster of genes located in the 15q11.2q13 region, which are normally expressed only from the paternally-inherited allele due to genomic imprinting. PWS can result from a deletion of the 15q11.2q13 region on the paternally-inherited chromosome 15, maternal uniparental disomy, or imprinting defects. We report a patient with an atypical deletion within 15q11.2q13 and a PWS phenotype, including hypotonia, feeding difficulties, short stature, developmental delay, and dysmorphisms. She has a deletion from TUBGCP5 to SNURF-SNRPN (including the imprinting center) but not the SNORD region. These types of reports are crucial for further supporting the established role of the imprinting center in the pathophysiology and critical region of PWS.
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Affiliation(s)
- Jazmín Belén Martínez
- Department of Medical Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
| | - Josefina María Álvarez Arancedo
- Department of Medical Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
| | - Andrea Solari
- Department of Medical Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
| | - Aldana Claps
- Department of Molecular Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
| | - Tania Castro
- Department of Molecular Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
| | - Julieta Eva Laiseca
- Department of Molecular Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
| | - Melisa Taboas
- Department of Molecular Genetics, National Center for Medical Genetics, National Administration of Laboratories and Institutes of Health, Ministry of Health, Buenos Aires, Argentina
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3
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Manssen L, Krey I, Gburek-Augustat J, von Hagen C, Lemke JR, Merkenschlager A, Weigand H, Makowski C. Precision Medicine in Angelman Syndrome. Neuropediatrics 2025; 56:69-82. [PMID: 39168152 DOI: 10.1055/a-2399-0191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Angelman syndrome (AS) is a rare neurogenetic disorder caused by a loss of function of UBE3A on the maternal allele. Clinical features include severe neurodevelopmental delay, epilepsy, sleep disturbances, and behavioral disorders. Therapy currently evolves from conventional symptomatic, supportive, and antiseizure treatments toward alteration of mRNA expression, which is subject of several ongoing clinical trials.This article will provide an overview of clinical research and therapeutic approaches on AS.
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Affiliation(s)
- Lena Manssen
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Ilona Krey
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Janina Gburek-Augustat
- Division of Neuropediatrics, Hospital for Children and Adolescents, Department of Women and Child Health, University of Leipzig, Leipzig, Germany
| | - Cornelia von Hagen
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
- Kinderzentrum Munchen gemeinnutzige GmbH, kbo, Munich, Germany
| | - Johannes R Lemke
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Andreas Merkenschlager
- Division of Neuropediatrics, Hospital for Children and Adolescents, Department of Women and Child Health, University of Leipzig, Leipzig, Germany
| | - Heike Weigand
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Christine Makowski
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
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4
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Rohm D, Black JB, McCutcheon SR, Barrera A, Berry SS, Morone DJ, Nuttle X, de Esch CE, Tai DJC, Talkowski ME, Iglesias N, Gersbach CA. Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editing. CELL GENOMICS 2025; 5:100770. [PMID: 39947136 PMCID: PMC11872474 DOI: 10.1016/j.xgen.2025.100770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 10/01/2024] [Accepted: 01/17/2025] [Indexed: 02/19/2025]
Abstract
Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi syndrome (PWS) results from loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control the expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.
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Affiliation(s)
- Dahlia Rohm
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Joshua B Black
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Sean R McCutcheon
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Alejandro Barrera
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
| | - Shanté S Berry
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Daniel J Morone
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Xander Nuttle
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Celine E de Esch
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Derek J C Tai
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Michael E Talkowski
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Nahid Iglesias
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Charles A Gersbach
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
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5
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Liu B, Wu T, Miao BA, Ji F, Liu S, Wang P, Zhao Y, Zhong Y, Sundaram A, Zeng TB, Majcherska-Agrawal M, Keenan RJ, Pan T, He C. snoRNA-facilitated protein secretion revealed by transcriptome-wide snoRNA target identification. Cell 2025; 188:465-483.e22. [PMID: 39579764 PMCID: PMC11761385 DOI: 10.1016/j.cell.2024.10.046] [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: 03/15/2024] [Revised: 09/13/2024] [Accepted: 10/24/2024] [Indexed: 11/25/2024]
Abstract
Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2'-O-methylation (Nm) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective technologies that identify snoRNA targets transcriptome wide. Here, we develop a chemical crosslinking-based approach that comprehensively detects cellular RNA targets of snoRNAs, yielding thousands of previously unrecognized snoRNA-mRNA interactions in human cells and mouse brain tissues. Many interactions occur outside of snoRNA-guided RNA modification sites, hinting at non-canonical functions beyond RNA modification. We find that one of these snoRNAs, SNORA73, targets mRNAs that encode secretory proteins and membrane proteins. SNORA73 also interacts with 7SL RNA, part of the signal recognition particle (SRP) required for protein secretion. The mRNA-SNORA73-7SL RNA interactions enhance the association of the SNORA73-target mRNAs with SRP, thereby facilitating the secretion of encoded proteins.
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Affiliation(s)
- Bei Liu
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Tong Wu
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Bernadette A Miao
- Howard Hughes Medical Institute, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA
| | - Fei Ji
- Howard Hughes Medical Institute, Chicago, IL 60637, USA; Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA
| | - Shun Liu
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Pingluan Wang
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Yutao Zhao
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Yuhao Zhong
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Arunkumar Sundaram
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Tie-Bo Zeng
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Marta Majcherska-Agrawal
- Howard Hughes Medical Institute, Chicago, IL 60637, USA; Committee on Genetics, Genomics & System Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Robert J Keenan
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Tao Pan
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
| | - Chuan He
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA; Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
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Wu H, Liu CX, Chen LL. Beyond housekeeping: a new role of snoRNA in nascent protein secretion. Cell Res 2025:10.1038/s41422-024-01070-8. [PMID: 39828808 DOI: 10.1038/s41422-024-01070-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025] Open
Affiliation(s)
- Hao Wu
- Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Chu-Xiao Liu
- Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ling-Ling Chen
- Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
- School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- New Cornerstone Science Laboratory, Shenzhen, Guangdong, China.
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Qadri SW, Shah NM, Muddashetty RS. Epitranscriptome-Mediated Regulation of Neuronal Translation. WILEY INTERDISCIPLINARY REVIEWS. RNA 2025; 16:e70004. [PMID: 39963903 DOI: 10.1002/wrna.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 12/02/2024] [Accepted: 01/24/2025] [Indexed: 04/10/2025]
Abstract
Epitranscriptomic modification of RNA is an important layer of regulation for gene expression. RNA modifications come in many flavors and generate a complex tapestry of a regulatory network. Here, we focus on two major RNA modifications, one on rRNA (2'O Methylation) and another on mRNA (N6-Methyladenosine [m6A]) and their impact on translation. The 2'O methyl group addition on the ribose sugar of rRNA plays a critical role in RNA folding, ribosome assembly, and its interaction with many RNA binding proteins. Differential methylation of these sites contributes to ribosome heterogeneity and generates potential "specialized ribosomes." Specialized ribosomes are proposed to play a variety of important roles in maintaining pluripotency, lineage specification, and compartmentalized and activity-mediated translation in neurons. The m6A modification, on the other hand, determines the stability, transport, and translation of subclasses of mRNA. The dynamic nature of m6A owing to the localization and activity of its writers, readers, and erasers makes it a powerful tool for spatiotemporal regulation of translation. While substantial information has accumulated on the nature and abundance of these modifications, their functional consequences are still understudied. In this article, we review the literature constructing the body of our understanding of these two modifications and their outcome on the regulation of translation in general and their impact on the nervous system in particular. We also explore the possibility of how these modifications may collaborate in modulating translation and provoke the thought to integrate the functions of multiple epitranscriptome modifications.
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Affiliation(s)
- Syed Wasifa Qadri
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Nisa Manzoor Shah
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Ravi S Muddashetty
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
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Zaric V, Kang HR, Rybalchenko V, Zigman JM, Gray SJ, Butler RK. RNAi Knockdown of EHMT2 in Maternal Expression of Prader-Willi Syndrome Genes. Genes (Basel) 2024; 15:1366. [PMID: 39596566 PMCID: PMC11594117 DOI: 10.3390/genes15111366] [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: 09/11/2024] [Revised: 10/13/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader-Willi Syndrome (PWS)-related genes, such as SNRPN and SNORD116, are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC. Here, we measured the effects of RNA interference of EHMT2 on the maternal expression of genes deficient in PWS in mouse model and patient iPSC-derived cells. METHODS We used small interfering RNA (siRNA) oligonucleotides and lentiviral short harpin RNA (shRNA) to reduce Ehtm2/EHMT2 expression in mouse Snord116 deletion primary neurons, PWS patient-derived induced pluripotent stem cell (iPSC) line and PWS iPSC-derived neurons. We then measured the expression of transcript or protein (if relevant) of PWS genes normally silenced on the maternal allele. RESULTS With an approximate reduction of 90% in EHMT2 mRNA and more than 80% of the EHMT2 protein, we demonstrated close to a 2-fold increase in the expression of maternal transcripts for SNRPN and SNORD116 in PWS iPSCs treated with siEHMT2 compared to PWS iPSC siControl. A similar increase in SNORD116 and SNRPN RNA expression was observed in PWS iPSC-derived neurons treated with shEHMT2. CONCLUSIONS RNAi reduction in EHMT2 activates maternally silenced PWS genes. Further studies are needed to determine whether the increase is therapeutically relevant. This study confirms the role of EHMT2 in the epigenetic regulation of PWS genes.
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Affiliation(s)
- Violeta Zaric
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390, USA; (V.Z.); (V.R.); (J.M.Z.)
| | - Hye Ri Kang
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA; (H.R.K.); (S.J.G.)
| | - Volodymyr Rybalchenko
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390, USA; (V.Z.); (V.R.); (J.M.Z.)
| | - Jeffrey M. Zigman
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390, USA; (V.Z.); (V.R.); (J.M.Z.)
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA; (H.R.K.); (S.J.G.)
- O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Steven J. Gray
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA; (H.R.K.); (S.J.G.)
- O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ryan K. Butler
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390, USA; (V.Z.); (V.R.); (J.M.Z.)
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA; (H.R.K.); (S.J.G.)
- O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
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Gutierrez Fugón OJ, Sharifi O, Heath N, Soto DC, Gomez JA, Yasui DH, Mendiola AJP, O’Geen H, Beitnere U, Tomkova M, Haghani V, Dillon G, Segal DJ, LaSalle JM. Integration of CTCF loops, methylome, and transcriptome in differentiating LUHMES as a model for imprinting dynamics of the 15q11-q13 locus in human neurons. Hum Mol Genet 2024; 33:1711-1725. [PMID: 39045627 PMCID: PMC11413648 DOI: 10.1093/hmg/ddae111] [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: 03/20/2024] [Revised: 06/30/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024] Open
Abstract
Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that terminates at PWAR1 in non-neurons. qRT-PCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11 834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
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Affiliation(s)
- Orangel J Gutierrez Fugón
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
| | - Osman Sharifi
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
| | - Nicholas Heath
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
| | - Daniela C Soto
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, 757 Westwood Plaza #4, Los Angeles, CA 90095, United States
| | - J Antonio Gomez
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
- Department of Natural Science, Seaver College, Pepperdine University, 24255 Pacific Coast Hwy, Malibu, CA 90263, United States
| | - Dag H Yasui
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
| | - Aron Judd P Mendiola
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
| | - Henriette O’Geen
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
| | - Ulrika Beitnere
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
- Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
| | - Marketa Tomkova
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
- Ludwig Cancer Research Center, University of Oxford, Old Road Campus Research Build, Roosevelt Dr, Headington, Oxford OX3 7DQ, United Kingdom
| | - Viktoria Haghani
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
| | - Greg Dillon
- Genetics and Neurodevelopmental Disorders Unit, Biogen, 225 Binney Street Cambridge, MA 02142 United States
| | - David J Segal
- Genome Center, Department of Biochemistry and Molecular Medicine, University of California Davis, 451 Health Sciences Dr., Davis, CA 95616, United States
| | - Janine M LaSalle
- Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, 1275 Med Science Dr, Davis, CA 95616, United States
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10
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Rahman ML, Bonnard AA, Wang F, Ruaud L, Guimiot F, Li Y, Defer I, Wang Y, Marchand V, Motorin Y, Yao B, Drunat S, Ghalei H. New ZNHIT3 Variants Disrupting snoRNP Assembly Cause Prenatal PEHO Syndrome with Isolated Hydrops. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.08.26.24312490. [PMID: 39252897 PMCID: PMC11383450 DOI: 10.1101/2024.08.26.24312490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
ZNHIT3 (zinc finger HIT type containing protein 3) is an evolutionarily conserved protein required for ribosome biogenesis by mediating the assembly of small nucleolar RNAs (snoRNAs) of class C/D into ribonucleoprotein complexes (snoRNPs). Missense mutations in the gene encoding ZNHIT3 protein have been previously reported to cause PEHO syndrome, a severe neurodevelopmental disorder typically presenting after birth. We discuss here the case of two fetuses from a single family who presented with isolated hydrops during the early second trimester of pregnancy, resulting in intrauterine demise. Autopsy revealed no associated malformation. Through whole-genome quartet analysis, we identified two novel variants within the ZNHIT3 gene, both inherited from healthy parents and occurring as compound heterozygotes in both fetuses. The c.40T>C p.Cys14Arg variant originated from the father, while the c.251_254delAAGA variant was of maternal origin. Analysis of the variants in human cell culture models reveals that both variants reduce cell growth, albeit to different extents, and impact the protein's stability and function in distinct ways. The c.251_254delAAGA results in production of a stable form of ZNHIT3 that lacks a domain required for mediating snoRNP biogenesis, whereas the c.40T>C p.Cys14Arg variation behaves similarly to the previously described PEHO-associated ZNHIT3 variants that destabilize the protein. Interestingly, both variations lead to a marked decrease in specific box C/D snoRNA levels, reduced rRNA levels and cellular translation. Analysis of rRNA methylation pattern in fetus samples reveals distinct sites of hypo 2'-O-methylation. RNA-seq analysis of undifferentiated and differentiated SHSY5Y cells transfected with the ZNHIT3 variants reveals differential expression of a set of genes, many of which are associated with developmental processes and RNA binding compared to cells expressing wild-type ZNHIT3. In summary, this work extends the phenotype of PEHO syndrome to include antenatal manifestations and describe the molecular defects induced by two novel ZNHIT3 variants.
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Affiliation(s)
- Md Lutfur Rahman
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Adeline A. Bonnard
- Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- INSERM UMR 1131, Saint-Louis Research Institute, Paris University, Paris, France
| | - Feng Wang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Lyse Ruaud
- Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- INSERM UMR 1141, Paris-Cité University, NeuroDiderot, Paris, France
| | - Fabien Guimiot
- Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- INSERM UMR 1141, Paris-Cité University, NeuroDiderot, Paris, France
| | - Yangping Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Ines Defer
- Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- INSERM UMR 1131, Saint-Louis Research Institute, Paris University, Paris, France
| | - Yilin Wang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Virginie Marchand
- Université de Lorraine, SMP IBSLor, Biopôle, 9 Avenue de la Forêt de Haye, Vandoeuvre-les-Nancy, France
| | - Yuri Motorin
- Université de Lorraine, UMR7365 IMoPA, CNRS, Biopôle, 9 Avenue de la Forêt de Haye, Vandoeuvre-les-Nancy, France
| | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Séverine Drunat
- Département de Génétique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- INSERM UMR 1141, Paris-Cité University, NeuroDiderot, Paris, France
| | - Homa Ghalei
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA
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11
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Wang SE, Xiong Y, Jang MA, Park KS, Donahue M, Velez J, Jin J, Jiang YH. Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome. Mol Ther 2024; 32:2662-2675. [PMID: 38796700 PMCID: PMC11405540 DOI: 10.1016/j.ymthe.2024.05.034] [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: 12/28/2023] [Revised: 03/29/2024] [Accepted: 05/23/2024] [Indexed: 05/28/2024] Open
Abstract
Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concept of epigenetic therapy in humans. The premise is that epigenetic modulations could reactivate the repressed PWS candidate genes from the maternal chromosome and offer therapeutic benefit. Our prior study identifies an EHMT2/G9a inhibitor, UNC0642, that reactivates the expression of PWS genes via reduction of H3K9me2. However, low brain permeability and poor oral bioavailability of UNC0642 preclude its advancement into translational studies in humans. In this study, a newly developed inhibitor, MS152, modified from the structure of UNC0642, has better brain penetration and greater potency and selectivity against EHMT2/G9a. MS152 reactivated maternally silenced PWS genes in PWS patient fibroblasts and in brain and liver tissues of PWS mouse models. Importantly, the molecular efficacy of oral administration is comparable with the intraperitoneal route. MS152 treatment in newborns ameliorates the perinatal lethality and poor growth, maintaining reactivation in a PWS mouse model at postnatal 90 days. Our findings provide strong support for MS152 as a first-in-class inhibitor to advance the epigenetic therapy of PWS in humans.
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Affiliation(s)
- Sung Eun Wang
- Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA
| | - Yan Xiong
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mi-Ae Jang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Kwang-Su Park
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Meaghan Donahue
- Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA
| | - Julia Velez
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Yong-Hui Jiang
- Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA.
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12
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Heimdörfer D, Vorleuter A, Eschlböck A, Spathopoulou A, Suarez-Cubero M, Farhan H, Reiterer V, Spanjaard M, Schaaf CP, Huber LA, Kremser L, Sarg B, Edenhofer F, Geley S, de Araujo MEG, Huettenhofer A. Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes. Am J Hum Genet 2024; 111:1383-1404. [PMID: 38908375 PMCID: PMC11267527 DOI: 10.1016/j.ajhg.2024.05.023] [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: 04/16/2024] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/24/2024] Open
Abstract
The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.
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Affiliation(s)
- David Heimdörfer
- Institute of Genomics and RNomics, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
| | - Alexander Vorleuter
- Institute of Genomics and RNomics, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Alexander Eschlböck
- Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria
| | - Angeliki Spathopoulou
- Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria
| | - Marta Suarez-Cubero
- Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria
| | - Hesso Farhan
- Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Veronika Reiterer
- Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Melanie Spanjaard
- Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Christian P Schaaf
- Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Lukas A Huber
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innrain 80/82, Innsbruck 6020, Austria
| | - Leopold Kremser
- Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Bettina Sarg
- Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Frank Edenhofer
- Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria
| | - Stephan Geley
- Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Mariana E G de Araujo
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innrain 80/82, Innsbruck 6020, Austria
| | - Alexander Huettenhofer
- Institute of Genomics and RNomics, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
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13
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Rohm D, Black JB, McCutcheon SR, Barrera A, Morone DJ, Nuttle X, de Esch CE, Tai DJ, Talkowski ME, Iglesias N, Gersbach CA. Activation of the imprinted Prader-Willi Syndrome locus by CRISPR-based epigenome editing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.03.583177. [PMID: 38496583 PMCID: PMC10942373 DOI: 10.1101/2024.03.03.583177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi Syndrome (PWS) is caused by loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.
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Affiliation(s)
- Dahlia Rohm
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Joshua B. Black
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Sean R. McCutcheon
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Alejandro Barrera
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
| | - Daniel J. Morone
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Xander Nuttle
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Celine E. de Esch
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Derek J.C. Tai
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Michael E. Talkowski
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Nahid Iglesias
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
| | - Charles A. Gersbach
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27708, USA
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
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14
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Zhang L, Guo H, Zhang X, Wang L, Wei F, Zhao Y, Wang B, Meng Y, Li Y. Small nucleolar RNA Snora73 promotes psoriasis progression by sponging miR-3074-5p and regulating PBX1 expression. Funct Integr Genomics 2024; 24:15. [PMID: 38240925 PMCID: PMC10799104 DOI: 10.1007/s10142-024-01300-7] [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: 11/07/2023] [Revised: 01/11/2024] [Accepted: 01/13/2024] [Indexed: 01/22/2024]
Abstract
Chronic psoriasis is a kind of immune-mediated skin illness and the underlying molecular mechanisms of pathogenesis remain incompletely understood. Here, we used small RNA microarray assays to scan the differential expressed RNAs in psoriasis patient samples. The downstream miRNAs and its targets were predicted using bioinformatics analysis from online bases and confirmed using fluorescence in situ hybridization and dual‑luciferase report gene assay. Cell ability of proliferation and migration were detected using CCK-8 and transwell assays. The results showed that a new snoRNA Snora73 was upregulated in psoriasis patient samples. Overexpression of Snora73 significantly increased psoriasis cells viability and migration, while knockdown of Snora73 got the opposite results. Mechanistically, our results showed that Snora73 acted as a sponge for miR-3074-5p and PBX1 is a direct target of miR-3074-5p in psoriasis cells. Furthermore, miR-3074-5p suppressed psoriasis cell proliferation and migration, while PBX1 promoted cell proliferation and migration in psoriasis. Collectively, these findings reveal a crucial role of Snora73 in progression of psoriasis through miR-3074-5p/PBX1 signaling pathway and suggest a potential therapeutic strategy.
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Affiliation(s)
- Lihua Zhang
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Hui Guo
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaoguang Zhang
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Ling Wang
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Feng Wei
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yike Zhao
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Bo Wang
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yibo Meng
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yanling Li
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
- Construction Unit of the Sub-Center of the National Center for Clinical Medical Research On Skin and Immunological Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
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15
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Lan YZ, Wu Z, Chen WJ, Fang ZX, Yu XN, Wu HT, Liu J. Small nucleolar RNA and its potential role in the oncogenesis and development of colorectal cancer. World J Gastroenterol 2024; 30:115-127. [PMID: 38312115 PMCID: PMC10835520 DOI: 10.3748/wjg.v30.i2.115] [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: 11/20/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Small nucleolar RNAs (snoRNAs) represent a class of non-coding RNAs that play pivotal roles in post-transcriptional RNA processing and modification, thereby contributing significantly to the maintenance of cellular functions related to protein synthesis. SnoRNAs have been discovered to possess the ability to influence cell fate and alter disease progression, holding immense potential in controlling human diseases. It is suggested that the dysregulation of snoRNAs in cancer exhibits differential expression across various cancer types, stages, metastasis, treatment response and/or prognosis in patients. On the other hand, colorectal cancer (CRC), a prevalent malignancy of the digestive system, is characterized by high incidence and mortality rates, ranking as the third most common cancer type. Recent research indicates that snoRNA dysregulation is associated with CRC, as snoRNA expression significantly differs between normal and cancerous conditions. Consequently, assessing snoRNA expression level and function holds promise for the prognosis and diagnosis of CRC. Nevertheless, current comprehension of the potential roles of snoRNAs in CRC remains limited. This review offers a comprehensive survey of the aberrant regulation of snoRNAs in CRC, providing valuable insights into the discovery of novel biomarkers, therapeutic targets, and potential tools for the diagnosis and treatment of CRC and furnishing critical cues for advancing research into CRC and the judicious selection of therapeutic targets.
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Affiliation(s)
- Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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16
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Tamir S, Dye TJ, Witt RM. Sleep and Circadian Disturbances in Children With Neurodevelopmental Disorders. Semin Pediatr Neurol 2023; 48:101090. [PMID: 38065637 DOI: 10.1016/j.spen.2023.101090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 12/18/2023]
Abstract
Sleep problems are highly prevalent in those with neurodevelopmental disorders (NDDs). We propose this is secondary to multiple factors that directly and indirectly negatively impact sleep and circadian processes in those with NDDs, which in turn, further perturbs development, resulting in a "developmental and sleep/circadian-related encephalopathy." In this review, we discuss select NDDs with known or suspected sleep and circadian phenotypes. We also highlight important considerations when evaluating and treating sleep and circadian disorders in these populations.
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Affiliation(s)
- Sharon Tamir
- University of Cincinnati College of Medicine, Cincinnati, OH; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Thomas J Dye
- Division of Child Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Division of Pulmonary Medicine and the Sleep Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Center for Circadian Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Rochelle M Witt
- Division of Child Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Division of Pulmonary Medicine and the Sleep Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Center for Circadian Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
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17
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Zhang M, Li K, Bai J, Van Damme R, Zhang W, Alba M, Stiles BL, Chen JF, Lu Z. A snoRNA-tRNA modification network governs codon-biased cellular states. Proc Natl Acad Sci U S A 2023; 120:e2312126120. [PMID: 37792516 PMCID: PMC10576143 DOI: 10.1073/pnas.2312126120] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/06/2023] [Indexed: 10/06/2023] Open
Abstract
The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA-protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA-tRNA interaction network that is required for global tRNA modifications, including 2'-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2'-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2'-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both single and double knockouts of D97 and D133 in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decades-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.
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Affiliation(s)
- Minjie Zhang
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
| | - Kongpan Li
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
| | - Jianhui Bai
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
| | - Ryan Van Damme
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
| | - Wei Zhang
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA90089
| | - Mario Alba
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
| | - Bangyan L. Stiles
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA90089
| | - Jian-Fu Chen
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA90089
| | - Zhipeng Lu
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA90089
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA90089
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18
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Gawade K, Raczynska KD. Imprinted small nucleolar RNAs: Missing link in development and disease? WILEY INTERDISCIPLINARY REVIEWS. RNA 2023:e1818. [PMID: 37722601 DOI: 10.1002/wrna.1818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/20/2023]
Abstract
The 14q32.2 (DLK1-DIO3) and 15q11-q13 (SNURF-SNRPN) imprinted gene loci harbor the largest known small nucleolar RNA clusters expressed from the respective maternal and paternal alleles. Recent studies have demonstrated significant roles for the 15q11-q13 located SNORD115-SNORD116 C/D box snoRNAs in Prader-Willi syndrome (PWS), a neurodevelopmental disorder. Even though the effect of SNORD116 deletion is apparent in the PWS phenotype, similar effects of a SNORD113-SNORD114 cluster deletion from the 14q32.2 locus in Kagami-Ogata syndrome (KOS14) and upregulation in Temple syndrome (TS14) remain to be explored. Moreover, apart from their probable involvement in neurodevelopmental disorders, snoRNAs from the SNORD113-SNORD114 cluster have been implicated in multiple biological processes, including pluripotency, development, cancers, and RNA modifications. Here we summarize the current understanding of the system to explore the possibility of a link between developmental disorders and C/D box snoRNA expression from the imprinted 14q32.2 locus. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development RNA Processing > Processing of Small RNAs.
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Affiliation(s)
- Kishor Gawade
- Laboratory of RNA Processing, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan, Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, Poznan, Poland
| | - Katarzyna D Raczynska
- Laboratory of RNA Processing, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan, Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, Poznan, Poland
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19
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Crenshaw MM, Graw SL, Slavov D, Boyle TA, Piqué DG, Taylor M, Baker P. An Atypical 15q11.2 Microdeletion Not Involving SNORD116 Resulting in Prader-Willi Syndrome. Case Rep Genet 2023; 2023:4225092. [PMID: 37736297 PMCID: PMC10511293 DOI: 10.1155/2023/4225092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/13/2023] [Accepted: 08/26/2023] [Indexed: 09/23/2023] Open
Abstract
Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS critical region contains four paternally expressed protein-coding genes along with small nucleolar RNA (snoRNA) genes under the control of the SNURF-SNRPN promoter, including the SNORD116 snoRNA gene cluster that is implicated in the PWS disease etiology. A 5-7 Mb deletion, maternal uniparental disomy, or an imprinting defect of chromosome 15q affect multiple genes in the PWS critical region, causing PWS. However, the individual contributions of these genes to the PWS phenotype remain elusive. Reports of smaller, atypical deletions may refine the boundaries of the PWS critical region or suggest additional disease-causing mechanisms. We describe an adult female with a classic PWS phenotype due to a 78 kb microdeletion that includes only exons 2 and 3 of SNURF-SNRPN with apparently preserved expression of SNORD116.
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Affiliation(s)
- Molly M. Crenshaw
- University of Colorado School of Medicine (CU-SOM), Department of Pediatrics, Section of Genetics and Metabolism, Aurora, Colorado, USA
| | - Sharon L. Graw
- Colorado Genetics Laboratory, Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Dobromir Slavov
- Division of Cardiology, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Theresa A. Boyle
- Department of Pathology, Stanford University, Palo Alto, California, USA
| | - Daniel G. Piqué
- University of Colorado School of Medicine (CU-SOM), Department of Pediatrics, Section of Genetics and Metabolism, Aurora, Colorado, USA
| | - Matthew Taylor
- Adult Medical Genetics Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Peter Baker
- University of Colorado School of Medicine (CU-SOM), Department of Pediatrics, Section of Genetics and Metabolism, Aurora, Colorado, USA
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20
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Hoyos Sanchez MC, Bayat T, Gee RRF, Fon Tacer K. Hormonal Imbalances in Prader-Willi and Schaaf-Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals. Int J Mol Sci 2023; 24:13109. [PMID: 37685915 PMCID: PMC10487939 DOI: 10.3390/ijms241713109] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/10/2023] Open
Abstract
The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader-Willi (PWS) and Schaaf-Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them, MAGEL2. Throughout life, PWS and SYS patients suffer from musculoskeletal deficiencies, intellectual disabilities, and hormonal abnormalities, which lead to compulsive behaviors like hyperphagia and temper outbursts. Management of PWS and SYS is mostly symptomatic and cures for these debilitating disorders do not exist, highlighting a clear, unmet medical need. Research over several decades into the molecular and cellular roles of PWS genes has uncovered that several impinge on the neuroendocrine system. In this review, we will discuss the expression and molecular functions of PWS genes, connecting them with hormonal imbalances in patients and animal models. Besides the observed hormonal imbalances, we will describe the recent findings about how the loss of individual genes, particularly MAGEL2, affects the molecular mechanisms of hormone secretion. These results suggest that MAGEL2 evolved as a mammalian-specific regulator of hypothalamic neuroendocrine function.
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Affiliation(s)
- Maria Camila Hoyos Sanchez
- School of Veterinary Medicine, Texas Tech University, 7671 Evans Dr., Amarillo, TX 79106, USA
- Texas Center for Comparative Cancer Research (TC3R), Amarillo, TX 79106, USA
| | - Tara Bayat
- School of Veterinary Medicine, Texas Tech University, 7671 Evans Dr., Amarillo, TX 79106, USA
- Texas Center for Comparative Cancer Research (TC3R), Amarillo, TX 79106, USA
| | - Rebecca R. Florke Gee
- School of Veterinary Medicine, Texas Tech University, 7671 Evans Dr., Amarillo, TX 79106, USA
- Texas Center for Comparative Cancer Research (TC3R), Amarillo, TX 79106, USA
| | - Klementina Fon Tacer
- School of Veterinary Medicine, Texas Tech University, 7671 Evans Dr., Amarillo, TX 79106, USA
- Texas Center for Comparative Cancer Research (TC3R), Amarillo, TX 79106, USA
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21
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Wang SE, Jiang YH. Novel epigenetic molecular therapies for imprinting disorders. Mol Psychiatry 2023; 28:3182-3193. [PMID: 37626134 PMCID: PMC10618104 DOI: 10.1038/s41380-023-02208-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 08/27/2023]
Abstract
Genomic imprinting disorders are caused by the disruption of genomic imprinting processes leading to a deficit or increase of an active allele. Their unique molecular mechanisms underlying imprinted genes offer an opportunity to investigate epigenetic-based therapy for reactivation of an inactive allele or reduction of an active allele. Current treatments are based on managing symptoms, not targeting the molecular mechanisms underlying imprinting disorders. Here, we highlight molecular approaches of therapeutic candidates in preclinical and clinical studies for individual imprinting disorders. These include the significant progress of discovery and testing of small molecules, antisense oligonucleotides, and CRISPR mediated genome editing approaches as new therapeutic strategies. We discuss the significant challenges of translating these promising therapies from the preclinical stage to the clinic, especially for genome editing based approaches.
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Affiliation(s)
- Sung Eun Wang
- Department of Genetics, Yale University School of Medicine, 333 Cedar street, New Haven, CT, 06520, USA
| | - Yong-Hui Jiang
- Department of Genetics, Yale University School of Medicine, 333 Cedar street, New Haven, CT, 06520, USA.
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar street, New Haven, CT, 06520, USA.
- Department of Pediatrics, Yale University School of Medicine, 333 Cedar street, New Haven, CT, 06520, USA.
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22
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Osborne-Lawrence S, Lawrence C, Metzger NP, Klavon J, Baig HR, Richard C, Varshney S, Gupta D, Singh O, Ogden SB, Shankar K, Paul S, Butler RK, Zigman JM. Effects of thermoneutrality on food intake, body weight, and body composition in a Prader-Willi syndrome mouse model. Obesity (Silver Spring) 2023; 31:1644-1654. [PMID: 37161883 PMCID: PMC12002079 DOI: 10.1002/oby.23766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/28/2023] [Accepted: 02/28/2023] [Indexed: 05/11/2023]
Abstract
OBJECTIVE Prader-Willi syndrome (PWS) is a multisystem genetic disorder. Unfortunately, none of several mouse models carrying PWS mutations emulates the entirety of the human PWS phenotype, including hyperphagia plus obesity. METHODS To determine whether housing at thermoneutrality (TN, 30 °C) permits the development of hyperphagia and obesity in the Snord116del PWS mouse model, the effects of housing three different ages of Snord116del and wild-type (WT) littermates at TN versus room temperature (RT, 22-24 °C) for 8 weeks were compared. RESULTS Snord116del mice born and maintained at TN exhibited lower body weight curves, lower percentage fat mass, and lower food intake than WT mice at RT. In 4- to 6-month-old high-fat diet-fed female mice, TN raised the Snord116del body weight curve closer to that of RT-housed WT mice although the TN-housed Snord116del mice did not gain more adiposity or exhibit greater food intake. In 6- to 8-month-old high-fat diet-fed male mice, body weight, adiposity, and food intake of TN-housed Snord116del mice remained far below levels in RT-housed WT mice. TN elicited hypotonia in Snord116del adults and exacerbated mortality of Snord116del newborns. CONCLUSIONS In none of three tested TN protocols were greater food intake, body weight, or adiposity induced in Snord116del mice compared with RT-housed WT mice.
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Affiliation(s)
- Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Connor Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Nathan P. Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Julia Klavon
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Hassan R. Baig
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Corine Richard
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Omprakash Singh
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sean B. Ogden
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Subhojit Paul
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Ryan K. Butler
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
- O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, Texas, USA
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
- O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, Texas, USA
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23
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Dindot SV, Christian S, Murphy WJ, Berent A, Panagoulias J, Schlafer A, Ballard J, Radeva K, Robinson R, Myers L, Jepp T, Shaheen H, Hillman P, Konganti K, Hillhouse A, Bredemeyer KR, Black L, Douville J. An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript. Sci Transl Med 2023; 15:eabf4077. [PMID: 36947593 DOI: 10.1126/scitranslmed.abf4077] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. The paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense (UBE3A-AS) transcript, which represents the distal end of the small nucleolar host gene 14 (SNHG14) transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the UBE3A-AS transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human UBE3A-AS transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of UBE3A-AS, reactivating the expression of the paternal UBE3A allele in neurotypical and Angelman syndrome induced pluripotent stem cell-derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress UBE3A-AS and reactivate the expression of the paternal UBE3A allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281).
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Affiliation(s)
- Scott V Dindot
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA
- GeneTx Biotherapeutics LLC, Sarasota, FL 34233, USA
- Research Department, Ultragenyx Pharmaceutical, Novato, CA 94949, USA
| | - Sarah Christian
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - William J Murphy
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | | | | | - Annalise Schlafer
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Johnathan Ballard
- Texas A&M Institute for Genomic Medicine (TIGM), Texas A&M University, College Station, TX 77843, USA
| | - Kamelia Radeva
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
- School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Ruth Robinson
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
- School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Luke Myers
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
- School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Thomas Jepp
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
- School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Hillary Shaheen
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Paul Hillman
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA
| | - Kranti Konganti
- Texas A&M University Institute for Genome Sciences and Society (TIGSS), Texas A&M University, College Station, TX 77843, USA
| | - Andrew Hillhouse
- Texas A&M University Institute for Genome Sciences and Society (TIGSS), Texas A&M University, College Station, TX 77843, USA
| | - Kevin R Bredemeyer
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | | | - Julie Douville
- Charles River Laboratories, Montreal, Senneville, Quebec H9X 1C1, Canada
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24
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Yu D, Zhang C, Zhou Y, Yang H, Peng C, Zhang F, Liao X, Zhu Y, Deng W, Li B, Zhang S. ncR2Met (lncR2metasta v2.0): An updated database for experimentally supported ncRNAs during cancer metastatic events. Genomics 2023; 115:110569. [PMID: 36736440 DOI: 10.1016/j.ygeno.2023.110569] [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: 11/22/2022] [Revised: 01/09/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023]
Abstract
Non-coding RNAs (ncRNAs) are widely involved in cancer metastatic events (CMEs, e.g., cancer cell invasion, intravasation, extravasation, proliferation), which collaboratively accelerate tumor spread and cause high patient mortality. In early 2020, we developed a manually curated database named 'lncR2metasta' to provide a comprehensive repository for long ncRNA (lncRNA) regulation during CMEs. We updated this database by supplementing other two important ncRNA types, microRNAs (miRNAs) and circular RNAs (circRNAs), for their involvement during CMEs after a thorough manual curation from published studies. ncR2metasta documents 1565 lncRNA-associated, 882 miRNA-associated, and 628 circRNA-associated entries for ncRNA-CME associations during 50 CMEs across 63 human cancer subtypes. ncR2Met has a concise web interface for researchers to easily browse, search and download as well as to submit novel ncRNA-CME associations. We anticipated that it could be a valuable resource, which will significantly improve our understanding of ncRNA functions in metastasis. It is freely available at http://ncr2met.wchoda.com.
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Affiliation(s)
- De'en Yu
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Cheng Zhang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yeman Zhou
- College of Science, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Heng Yang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Chen Peng
- School of Computer Science and Technology, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Feng Zhang
- School of Mathematics and Physics, China University of Geosciences, Wuhan 430074, China
| | - Xinghua Liao
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yuan Zhu
- School of Mathematics and Physics, China University of Geosciences, Wuhan 430074, China
| | - Wensheng Deng
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China.
| | - Bo Li
- School of Computer Science and Technology, Wuhan University of Science and Technology, Wuhan 430065, China.
| | - Shihua Zhang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China.
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25
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Gawade K, Plewka P, Häfner SJ, Lund AH, Marchand V, Motorin Y, Szczesniak MW, Raczynska KD. FUS regulates a subset of snoRNA expression and modulates the level of rRNA modifications. Sci Rep 2023; 13:2974. [PMID: 36806717 PMCID: PMC9941101 DOI: 10.1038/s41598-023-30068-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
FUS is a multifunctional protein involved in many aspects of RNA metabolism, including transcription, splicing, translation, miRNA processing, and replication-dependent histone gene expression. In this work, we show that FUS depletion results in the differential expression of numerous small nucleolar RNAs (snoRNAs) that guide 2'-O methylation (2'-O-Me) and pseudouridylation of specific positions in ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). Using RiboMeth-seq and HydraPsiSeq for the profiling of 2'-O-Me and pseudouridylation status of rRNA species, we demonstrated considerable hypermodification at several sites in HEK293T and SH-SY5Y cells with FUS knockout (FUS KO) compared to wild-type cells. We observed a similar direction of changes in rRNA modification in differentiated SH-SY5Y cells with the FUS mutation (R495X) related to the severe disease phenotype of amyotrophic lateral sclerosis (ALS). Furthermore, the pattern of modification of some rRNA positions was correlated with the abundance of corresponding guide snoRNAs in FUS KO and FUS R495X cells. Our findings reveal a new role for FUS in modulating the modification pattern of rRNA molecules, that in turn might generate ribosome heterogeneity and constitute a fine-tuning mechanism for translation efficiency/fidelity. Therefore, we suggest that increased levels of 2'-O-Me and pseudouridylation at particular positions in rRNAs from cells with the ALS-linked FUS mutation may represent a possible new translation-related mechanism that underlies disease development and progression.
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Affiliation(s)
- Kishor Gawade
- Laboratory of RNA Processing, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland
| | - Patrycja Plewka
- Laboratory of RNA Processing, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland
| | - Sophia J Häfner
- Biotech Research and Innovation Centre, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Anders H Lund
- Biotech Research and Innovation Centre, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Virginie Marchand
- Université de Lorraine, UAR2008/US40 IBSLor CNRS-INSERM and UMR7365 IMoPA CNRS, Nancy, France
| | - Yuri Motorin
- Université de Lorraine, UAR2008/US40 IBSLor CNRS-INSERM and UMR7365 IMoPA CNRS, Nancy, France
| | - Michal W Szczesniak
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland
| | - Katarzyna D Raczynska
- Laboratory of RNA Processing, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland.
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, 61-614, Poznan, Poland.
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26
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Gao Y, Yang LL, Dai YL, Shen Z, Zhou Q, Zou CC. Effects of early recombinant human growth hormone treatment in young Chinese children with Prader-Willi syndrome. Orphanet J Rare Dis 2023; 18:25. [PMID: 36750945 PMCID: PMC9906936 DOI: 10.1186/s13023-023-02615-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 01/15/2023] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND Prader-Willi syndrome (PWS) is a rare and multisystemic genetic disorder that is characterized by severe hypotonia, hyperphagia, short stature, and global developmental delay. Although early recombinant human growth hormone (rhGH) treatment has been proven to rescue some symptoms and bring additional benefits to PWS patients, studies in patients under 2 years old are scarce. Thus, this study aims to investigate the effectiveness and safety of rhGH treatment for young children. METHODS A total of 96 genetically confirmed Chinese PWS infants or toddlers (47 males) followed between 2013 and 2022 were retrospectively analyzed. Sixty-five infants (early treatment group) started rhGH treatment during their first year, and 31 toddlers (later treatment group) started at the age of 1-2 years. Auxological parameters, carbohydrate metabolism parameters, thyroid function, liver function, insulin-like growth factor-1 (IGF-1), and radiographs were acquired before the initiation of the treatment and every 3-6 months thereafter. Height/length, weight, and weight for height were expressed as standard deviation scores (SDSs) according to WHO child growth standards. RESULTS The mean SDS of length/height in the early treatment group was significantly higher than that in the later treatment group throughout the observation period (all P < 0.001). The change in the length SDS between the two groups at 1 year old and 4 years old was 1.50 (95% CI, 0.88-2.13) and 0.63 (95% CI, 0.16-1.10), respectively. Compared to the later treatment group, the weight SDS in the early treatment group increased by 0.94 (95% CI, 0.37-1.52) at 1 year old and 0.84 (95% CI, 0.28-1.39) at 2 years old. No statistical significance was found after 2.5 years of age. No significant differences were observed in IGF-1, incidence of liver dysfunction, hypothyroidism or spinal deformity between the two groups. CONCLUSIONS rhGH treatment improved growth and body composition in infants and toddlers. Furthermore, an early start of rhGH treatment is expected to have more efficacy than the later treatment group without an increase in adverse effects.
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Affiliation(s)
- Ying Gao
- grid.411360.1The Children’s Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, 310051 China
| | - Li-Li Yang
- grid.411360.1The Children’s Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, 310051 China
| | - Yang-Li Dai
- grid.411360.1The Children’s Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, 310051 China
| | - Zheng Shen
- grid.411360.1The Children’s Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, 310051 China
| | - Qiong Zhou
- The Children's Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, 310051, China. .,Hangzhou children's Hospital, No. 195 Wenhui Road, Hangzhou, 310000, China.
| | - Chao-Chun Zou
- The Children's Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, 310051, China.
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Marty V, Butler JJ, Coutens B, Chargui O, Chagraoui A, Guiard BP, De Deurwaerdère P, Cavaillé J. Deleting Snord115 genes in mice remodels monoaminergic systems activity in the brain toward cortico-subcortical imbalances. Hum Mol Genet 2023; 32:244-261. [PMID: 35951020 DOI: 10.1093/hmg/ddac139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/25/2022] [Accepted: 06/09/2022] [Indexed: 01/18/2023] Open
Abstract
The neuronal-specific SNORD115 has gathered interest because its deficiency may contribute to the pathophysiology of Prader-Willi syndrome (PWS), possibly by altering post-transcriptional regulation of the gene encoding the serotonin (HTR2C) receptor. Yet, Snord115-KO mice do not resume the main symptoms of PWS, and only subtle-altered A-to-I RNA editing of Htr2c mRNAs was uncovered. Because HTR2C signaling fine-tunes the activity of monoaminergic neurons, we addressed the hypothesis that lack of Snord115 alters monoaminergic systems. We first showed that Snord115 was expressed in both monoaminergic and non-monoaminergic cells of the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN) harboring cell bodies of dopaminergic and serotonergic neurons, respectively. Measuring the tissue level of monoamines and metabolites, we found very few differences except that the content of homovanillic acid-a metabolite of dopamine-was decreased in the orbitofrontal and prefrontal cortex of Snord115-KO mice. The latter effects were, however, associated with a few changes in monoamine tissue content connectivity across the 12 sampled brain regions. Using in vivo single-cell extracellular recordings, we reported that the firing rate of VTA dopaminergic neurons and DRN serotonergic neurons was significantly increased in Snord115-KO mice. These neural circuit dysfunctions were not, however, associated with apparent defects in binge eating, conditioned place preference to cocaine, cocaine-induced hyperlocomotion or compulsive behavior. Altogether, our multiscale study shows that the absence of Snord115 impacts central monoaminergic circuits to an extent that does not elicit gross behavioral abnormalities.
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Affiliation(s)
- Virginie Marty
- Molecular, Cellular and Developmental Biology (MCD) unit, Center of Integrative Biology (CBI), CNRS - University of Toulouse; CNRS, UPS, 31 062 Toulouse, France
| | - Jasmine J Butler
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA), CNRS-UMR 5287, 146 rue Léo Saignat, B.P.281, F-33000 Bordeaux Cedex, France
| | - Basile Coutens
- Research Center on Animal Cognition (CRCA), Center of Integrative Biology (CBI), CNRS - University of Toulouse; CNRS, UPS, 31 062 Toulouse, France
| | - Oumaima Chargui
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA), CNRS-UMR 5287, 146 rue Léo Saignat, B.P.281, F-33000 Bordeaux Cedex, France
| | - Abdeslam Chagraoui
- Différenciation et Communication Neuroendocrine, Endocrine et Germinale (NorDic), INSERM U1239, IRIB, CHU Rouen, 76 000 Rouen, France.,Department of Medical Biochemistry, Rouen University Hospital, 76 000 Rouen, France
| | - Bruno P Guiard
- Research Center on Animal Cognition (CRCA), Center of Integrative Biology (CBI), CNRS - University of Toulouse; CNRS, UPS, 31 062 Toulouse, France
| | - Philippe De Deurwaerdère
- Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA), CNRS-UMR 5287, 146 rue Léo Saignat, B.P.281, F-33000 Bordeaux Cedex, France
| | - Jérôme Cavaillé
- Molecular, Cellular and Developmental Biology (MCD) unit, Center of Integrative Biology (CBI), CNRS - University of Toulouse; CNRS, UPS, 31 062 Toulouse, France
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Webster SF, Ghalei H. Maturation of small nucleolar RNAs: from production to function. RNA Biol 2023; 20:715-736. [PMID: 37796118 PMCID: PMC10557570 DOI: 10.1080/15476286.2023.2254540] [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] [Accepted: 08/28/2023] [Indexed: 10/06/2023] Open
Abstract
Small Nucleolar RNAs (snoRNAs) are an abundant group of non-coding RNAs with well-defined roles in ribosomal RNA processing, folding and chemical modification. Besides their classic roles in ribosome biogenesis, snoRNAs are also implicated in several other cellular activities including regulation of splicing, transcription, RNA editing, cellular trafficking, and miRNA-like functions. Mature snoRNAs must undergo a series of processing steps tightly regulated by transiently associating factors and coordinated with other cellular processes including transcription and splicing. In addition to their mature forms, snoRNAs can contribute to gene expression regulation through their derivatives and degradation products. Here, we review the current knowledge on mechanisms of snoRNA maturation, including the different pathways of processing, and the regulatory mechanisms that control snoRNA levels and complex assembly. We also discuss the significance of studying snoRNA maturation, highlight the gaps in the current knowledge and suggest directions for future research in this area.
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Affiliation(s)
- Sarah F. Webster
- Biochemistry, Cell, and Developmental Biology Graduate Program, Emory University, Atlanta, Georgia, USA
- Department of Biochemistry, Emory University, Atlanta, Georgia, USA
| | - Homa Ghalei
- Department of Biochemistry, Emory University, Atlanta, Georgia, USA
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Xuan C, Yang E, Zhao S, Xu J, Li P, Zhang Y, Jiang Z, Ding X. Regulation of LncRNAs and microRNAs in neuronal development and disease. PeerJ 2023; 11:e15197. [PMID: 37038472 PMCID: PMC10082570 DOI: 10.7717/peerj.15197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 03/15/2023] [Indexed: 04/12/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are RNAs that do not encode proteins but play important roles in regulating cellular processes. Multiple studies over the past decade have demonstrated the role of microRNAs (miRNAs) in cancer, in which some miRNAs can act as biomarkers or provide therapy target. Accumulating evidence also points to the importance of long non-coding RNAs (lncRNAs) in regulating miRNA-mRNA networks. An increasing number of ncRNAs have been shown to be involved in the regulation of cellular processes, and dysregulation of ncRNAs often heralds disease. As the population ages, the incidence of neurodegenerative diseases is increasing, placing enormous pressure on global health systems. Given the excellent performance of ncRNAs in early cancer screening and treatment, here we attempted to aggregate and analyze the regulatory functions of ncRNAs in neuronal development and disease. In this review, we summarize current knowledge on ncRNA taxonomy, biogenesis, and function, and discuss current research progress on ncRNAs in relation to neuronal development, differentiation, and neurodegenerative diseases.
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Affiliation(s)
- Cheng Xuan
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Enyu Yang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Shuo Zhao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Juan Xu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Peihang Li
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Yaping Zhang
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang Province, China
| | - Zhenggang Jiang
- Department of Science Research and Information Management, Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, Zhejiang Province, China
| | - Xianfeng Ding
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
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Saini A, Varshney A, Saini A, Mani I. Insight into epigenetics and human diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:1-21. [PMID: 37019588 DOI: 10.1016/bs.pmbts.2023.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
The most eminent research of the 21st century whirls around the epigenetic and the variability of DNA sequences in humans. The reciprocity between the epigenetic changes and the exogenous factors drives an influence on the inheritance biology and gene expression both inter-generationally and trans-generationally. Chromatin level modifications like DNA methylation, histone modifications or changes in transcripts functions either at transcription level or translational level pave the way for certain diseases or cancer in humans. The ability of epigenetics to explain the processes of various diseases has been demonstrated by recent epigenetic studies. Multidisciplinary therapeutic strategies were developed in order to analyse how epigenetic elements interact with different disease pathways. In this chapter we summarize how an organism may be predisposed to certain diseases by exposure to environmental variables such as chemicals, medications, stress, or infections during particular, vulnerable phases of life, and the epigenetic component may influence some of the diseases in humans.
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Comparison of Body Composition, Muscle Strength and Cardiometabolic Profile in Children with Prader-Willi Syndrome and Non-Alcoholic Fatty Liver Disease: A Pilot Study. Int J Mol Sci 2022; 23:ijms232315115. [PMID: 36499438 PMCID: PMC9739027 DOI: 10.3390/ijms232315115] [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: 11/01/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Syndromic and non-syndromic obesity conditions in children, such as Prader-Willi syndrome (PWS) and non-alcoholic fatty liver disease (NAFLD), both lower quality of life and increase risk for chronic health complications, which further increase health service utilization and cost. In a pilot observational study, we compared body composition and muscle strength in children aged 7−18 years with either PWS (n = 9), NAFLD (n = 14), or healthy controls (n = 16). Anthropometric and body composition measures (e.g., body weight, circumferences, skinfolds, total/segmental composition, and somatotype), handgrip strength, six minute-walk-test (6MWT), physical activity, and markers of liver and cardiometabolic dysfunction (e.g., ALT, AST, blood pressure, glucose, insulin, and lipid profile) were measured using standard procedures and validated tools. Genotyping was determined for children with PWS. Children with PWS had reduced lean body mass (total/lower limb mass), lower handgrip strength, 6MWT and increased sedentary activity compared to healthy children or those with NAFLD (p < 0.05). Children with PWS, including those of normal body weight, had somatotypes consistent with relative increased adiposity (endomorphic) and reduced skeletal muscle robustness (mesomorphic) when compared to healthy children and those with NAFLD. Somatotype characterizations were independent of serum markers of cardiometabolic dysregulation but were associated with increased prevalence of abnormal systolic and diastolic blood pressure Z-scores (p < 0.05). Reduced lean body mass and endomorphic somatotypes were associated with lower muscle strength/functionality and sedentary lifestyles, particularly in children with PWS. These findings are relevant as early detection of deficits in muscle strength and functionality can ensure effective targeted treatments that optimize physical activity and prevent complications into adulthood.
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Huang W, Sun YM, Pan Q, Fang K, Chen XT, Zeng ZC, Chen TQ, Zhu SX, Huang LB, Luo XQ, Wang WT, Chen YQ. The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1. Cell Discov 2022; 8:117. [PMID: 36316318 PMCID: PMC9622897 DOI: 10.1038/s41421-022-00460-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 08/18/2022] [Indexed: 01/24/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are usually 5' capped and 3' polyadenylated, similar to most typical mRNAs. However, recent studies revealed a type of snoRNA-related lncRNA with unique structures, leading to questions on how they are processed and how they work. Here, we identify a novel snoRNA-related lncRNA named LNC-SNO49AB containing two C/D box snoRNA sequences, SNORD49A and SNORD49B; and show that LNC-SNO49AB represents an unreported type of lncRNA with a 5'-end m7G and a 3'-end snoRNA structure. LNC-SNO49AB was found highly expressed in leukemia patient samples, and silencing LNC-SNO49AB dramatically suppressed leukemia progression in vitro and in vivo. Subcellular location indicated that the LNC-SNO49AB is mainly located in nucleolus and interacted with the nucleolar protein fibrillarin. However, we found that LNC-SNO49AB does not play a role in 2'-O-methylation regulation, a classical function of snoRNA; instead, its snoRNA structure affected the lncRNA stability. We further demonstrated that LNC-SNO49AB could directly bind to the adenosine deaminase acting on RNA 1(ADAR1) and promoted its homodimerization followed by a high RNA A-to-I editing activity. Transcriptome profiling shows that LNC-SNO49AB and ADAR1 knockdown respectively share very similar patterns of RNA modification change in downstream signaling pathways, especially in cell cycle pathways. These findings suggest a previously unknown class of snoRNA-related lncRNAs, which function via a manner in nucleolus independently on snoRNA-guide rRNA modification. This is the first report that a lncRNA regulates genome-wide RNA A-to-I editing by enhancing ADAR1 dimerization to facilitate hematopoietic malignancy, suggesting that LNC-SNO49AB may be a novel target in therapy directed to leukemia.
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Affiliation(s)
- Wei Huang
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Yu-Meng Sun
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Qi Pan
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Ke Fang
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Xiao-Tong Chen
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Zhan-Cheng Zeng
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Tian-Qi Chen
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Shun-Xin Zhu
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Li-Bin Huang
- grid.412615.50000 0004 1803 6239The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong China
| | - Xue-Qun Luo
- grid.412615.50000 0004 1803 6239The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong China
| | - Wen-Tao Wang
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Yue-Qin Chen
- grid.12981.330000 0001 2360 039XGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong China
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Oztan O, Zyga O, Stafford DEJ, Parker KJ. Linking oxytocin and arginine vasopressin signaling abnormalities to social behavior impairments in Prader-Willi syndrome. Neurosci Biobehav Rev 2022; 142:104870. [PMID: 36113782 PMCID: PMC11024898 DOI: 10.1016/j.neubiorev.2022.104870] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 09/06/2022] [Accepted: 09/12/2022] [Indexed: 11/19/2022]
Abstract
Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder. Global hypothalamic dysfunction is a core feature of PWS and has been implicated as a driver of many of PWS's phenotypic characteristics (e.g., hyperphagia-induced obesity, hypogonadism, short stature). Although the two neuropeptides (i.e., oxytocin [OXT] and arginine vasopressin [AVP]) most implicated in mammalian prosocial functioning are of hypothalamic origin, and social functioning is markedly impaired in PWS, there has been little consideration of how dysregulation of these neuropeptide signaling pathways may contribute to PWS's social behavior impairments. The present article addresses this gap in knowledge by providing a comprehensive review of the preclinical and clinical PWS literature-spanning endogenous neuropeptide measurement to exogenous neuropeptide administration studies-to better understand the roles of OXT and AVP signaling in this population. The preponderance of evidence indicates that OXT and AVP signaling are indeed dysregulated in PWS, and that these neuropeptide pathways may provide promising targets for therapeutic intervention in a patient population that currently lacks a pharmacological strategy for its debilitating social behavior symptoms.
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Affiliation(s)
- Ozge Oztan
- 1201 Welch Road, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Olena Zyga
- 1201 Welch Road, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Diane E J Stafford
- Center for Academic Medicine, 453 Quarry Road, Department of Pediatrics, Division of Pediatric Endocrinology, Stanford University, Palo Alto, CA 94304, USA
| | - Karen J Parker
- 1201 Welch Road, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; 300 Pasteur Drive, Department of Comparative Medicine, Stanford University, Stanford, CA 94305, USA.
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Whittington J, Holland A. Next Steps in Prader-Willi Syndrome Research: On the Relationship between Genotype and Phenotype. Int J Mol Sci 2022; 23:ijms232012089. [PMID: 36292940 PMCID: PMC9603642 DOI: 10.3390/ijms232012089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 12/02/2022] Open
Abstract
This article reviews what we know of the phenotype and genotype of Prader-Willi syndrome and hypothesizes two possible paths from phenotype to genotype. It then suggests research that may strengthen the case for one or other of these hypotheses.
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Affiliation(s)
- Joyce Whittington
- Correspondence: ; Tel.: +41 (0)1223 465255; Fax: +41 (0) 1223 465270
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Sledziowska M, Winczura K, Jones M, Almaghrabi R, Mischo H, Hebenstreit D, Garcia P, Grzechnik P. Non-coding RNAs associated with Prader-Willi syndrome regulate transcription of neurodevelopmental genes in human induced pluripotent stem cells. Hum Mol Genet 2022; 32:608-620. [PMID: 36084040 PMCID: PMC9896466 DOI: 10.1093/hmg/ddac228] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/05/2022] [Accepted: 09/03/2022] [Indexed: 02/07/2023] Open
Abstract
Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders, such as Prader-Willi syndrome (PWS), which results from the deletion of an imprinted locus on paternally inherited chromosome 15. We analyzed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5' snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance, while upregulated genes are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data reveal the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provide a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature, which is important for neuronal differentiation and development.
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Affiliation(s)
- Monika Sledziowska
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Kinga Winczura
- School of Biological Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK
| | - Matt Jones
- School of Life Sciences, Gibbet Hill Campus, University of Warwick, Coventry CV4 7AL, UK
| | - Ruba Almaghrabi
- Institute for Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Hannah Mischo
- School of Immunology & Microbial Sciences, King’s College London, London SE1 9RT, UK
| | - Daniel Hebenstreit
- School of Life Sciences, Gibbet Hill Campus, University of Warwick, Coventry CV4 7AL, UK
| | - Paloma Garcia
- Institute for Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK,Birmingham Centre for Genome Biology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Pawel Grzechnik
- To whom correspondence should be addressed at: School of Biological Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
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Osawa M, Ikeda H, Ueda A, Naito H, Nagao R, Kakimoto Y. Gastric aspiration in sudden unexpected infant death of Prader-Willi syndrome: immunohistochemical detection of feeding components. Int J Legal Med 2022; 136:1883-1888. [PMID: 36018383 PMCID: PMC9576639 DOI: 10.1007/s00414-022-02883-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022]
Abstract
Prader–Willi syndrome (PWS) in infants is characterized by hypotonia and poor sucking with feeding difficulties. Two autopsy cases of sudden unexpected death during sleep after tube feeding are described herein. For one, gastric aspiration caused by the possible milk regurgitation was suspected. Immunohistochemical examination of lung sections was performed using three antibodies to human α-lactalbumin, human gross cystic disease fluid protein 15, and cow whey β-lactoglobulin. Five cases of sudden unexpected infant death occurring earlier than at 6 months old were selected as controls. Marked immune-staining for infant formula in one PWS subject was evident within terminal bronchioles and alveoli with granular and amorphous features. However, no positive staining was apparent in the other subject, who exhibited contrasting features in milk distribution. Among control cases, one showed mild staining in the bronchiole, but the others did not. The antibody to β-lactoglobulin reacted specifically with formula, with no nonspecific background. Gastric contents in the airway can be a difficult issue because of the consequent terminal gasping. However, because of an episode of antemortem symptoms of potential regurgitation, and from findings at autopsy such as petechiae, we inferred that fatal regurgitation occurred in this PWS infant after tube feeding. Several clinical reports have described milk aspiration, but this pathological report is the first related to aspiration in PWS during tube feeding.
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Affiliation(s)
- Motoki Osawa
- Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
| | - Haruka Ikeda
- Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Atsushi Ueda
- Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Haruaki Naito
- Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Ryoko Nagao
- Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Yu Kakimoto
- Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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Atypical 15q11.2-q13 Deletions and the Prader-Willi Phenotype. J Clin Med 2022; 11:jcm11154636. [PMID: 35956251 PMCID: PMC9369699 DOI: 10.3390/jcm11154636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Prader-Willi syndrome (PWS) is a rare genetic disorder resulting from the lack of expression of the PWS region (locus q11-q13) on the paternally derived chromosome 15, as a result of a type I or II paternal deletion (50%), maternal uniparental disomy (43%), imprinting defect (4%) or translocation (<1%). In very rare cases, atypical deletions, smaller or larger than the typical deletion, are identified. These patients may have distinct phenotypical features and provide further information regarding the genotype−phenotype correlation in PWS. Methods: A prospective study in eight patients (six males and two females) with an atypical deletion in the PWS region accompanies an overview of reported cases. Results: All patients had hypotonia (100%) and many had typical PWS facial characteristics (75%), social and emotional developmental delays (75%), intellectual disabilities (50%), neonatal feeding problems and tube feeding (63%), history of obesity (50%), hyperphagia (50%) and scoliosis (50%). All males had cryptorchidism. Two patients had two separate deletions in the PWS critical region. Conclusions: Our findings provide further insight into PWS genotype−phenotype correlations; our results imply that inclusion of both SNURF-SNPRN and SNORD-116 genes in the deletion leads to a more complete PWS phenotype. A larger deletion, extending further upstream and downstream from these genes, does not cause a more severe phenotype. Conventional PWS methylation testing may miss small deletions, which can be identified using targeted next generation sequencing. PWS’s phenotypic diversity might be caused by differentially methylated regions outside the 15q11.2 locus.
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Reference Genes across Nine Brain Areas of Wild Type and Prader-Willi Syndrome Mice: Assessing Differences in Igfbp7, Pcsk1, Nhlh2 and Nlgn3 Expression. Int J Mol Sci 2022; 23:ijms23158729. [PMID: 35955861 PMCID: PMC9369261 DOI: 10.3390/ijms23158729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/18/2022] Open
Abstract
Prader−Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by the deletion or inactivation of paternally expressed imprinted genes at the chromosomal region 15q11−q13. The PWS-critical region (PWScr) harbors tandemly repeated non-protein coding IPW-A exons hosting the intronic SNORD116 snoRNA gene array that is predominantly expressed in brain. Paternal deletion of PWScr is associated with key PWS symptoms in humans and growth retardation in mice (PWScr model). Dysregulation of the hypothalamic−pituitary axis (HPA) is thought to be causally involved in the PWS phenotype. Here we performed a comprehensive reverse transcription quantitative PCR (RT-qPCR) analysis across nine different brain regions of wild-type (WT) and PWScr mice to identify stably expressed reference genes. Four methods (Delta Ct, BestKeeper, Normfinder and Genorm) were applied to rank 11 selected reference gene candidates according to their expression stability. The resulting panel consists of the top three most stably expressed genes suitable for gene-expression profiling and comparative transcriptome analysis of WT and/or PWScr mouse brain regions. Using these reference genes, we revealed significant differences in the expression patterns of Igfbp7, Nlgn3 and three HPA associated genes: Pcsk1, Pcsk2 and Nhlh2 across investigated brain regions of wild-type and PWScr mice. Our results raise a reasonable doubt on the involvement of the Snord116 in posttranscriptional regulation of Nlgn3 and Nhlh2 genes. We provide a valuable tool for expression analysis of specific genes across different areas of the mouse brain and for comparative investigation of PWScr mouse models to discover and verify different regulatory pathways affecting this complex disorder.
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Chen W, Ma C, Dong Y, Li S. The bovine Prader-Willi/Angelman imprinted domain has four Sno-lncRNAs types. Anim Genet 2022; 53:685-689. [PMID: 35844032 DOI: 10.1111/age.13244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/14/2022] [Accepted: 07/06/2022] [Indexed: 11/30/2022]
Abstract
Sno-lncRNAs are intron-derived long noncoding RNAs (lncRNAs) with snoRNA ends. Sno-lncRNAs were first discovered in the human Prader-Willi (PWS)/Angelman (AS) imprinted domain. Here, we report the identification and characterization of four sno-lncRNA types (sno-lncRNA1, sno-lncRNA2, sno-lncRNA3, and sno-lncRNA4) in the bovine PWS/AS imprinted domain. Reverse transcription-PCR first determined the cDNA sequences of the four bovine sno-lncRNAs. A gene structure analysis showed that sno-lncRNA1 lacks introns, but sno-lncRNA2 and sno-lncRNA3 have one and two introns respectively. The three sno-lncRNAs have similar snoRNA ends. Moreover, the three have similar snoRNAs at their 5' and 3' ends. The head-to-tail orientation has six sno-lncRNA copies arranged between bovine SNORD116-6 and SNORD116-12. Moreover, only a copy of sno-lncRNA4 was located between SNORD116-3 and SNORD116-4. The expression of the four sno-lncRNAs was analyzed in the bovine heart, liver, spleen, lung, kidney, muscle, fat, brain, and placenta tissues. The monoallelic expression of sno-lncRNA4 was determined in bovine tissues. The results showed that the four sno-lncRNAs are widely expressed in the nine tissues, although sno-lncRNA3 and sno-lncRNA4 were undetected in the placenta. Moreover, an informative single nucleotide polymorphism (rs448706424) revealed the allelic expression of sno-lncRNA4 in exon 2 of sno-lncRNA4. The bovine genome had six copies of sno-lncRNA1, sno-lncRNA2, and sno-lncRNA3, but their allelic expression was not identified.
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Affiliation(s)
- Weina Chen
- College of Traditional Chinese Medicine, Hebei University, Baoding, China
| | - Chao Ma
- Baoding NO.2 Hospital, Baoding, China
| | - Yanqiu Dong
- Department of Biochemistry and Molecular Biology, College of Life Science, Hebei Agriculture University, Baoding, China
| | - Shijie Li
- Department of Biochemistry and Molecular Biology, College of Life Science, Hebei Agriculture University, Baoding, China
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A Review of Prader–Willi Syndrome. ENDOCRINES 2022. [DOI: 10.3390/endocrines3020027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Prader–Willi Syndrome (PWS, OMIM #176270) is a rare complex genetic disorder due to the loss of expression of paternally derived genes in the PWS critical region on chromosome 15q11-q13. It affects multiple neuroendocrine systems and may present failure to thrive in infancy, but then, hyperphagia and morbid obesity starting in early childhood became the hallmark of this condition. Short stature, hypogonadism, sleep abnormalities, intellectual disability, and behavioral disturbances highlight the main features of this syndrome. There have been a significant number of advances in our understanding of the genetic mechanisms underlying the disease, especially discoveries of MAGEL2, NDN, MKRN3, and SNORD116 genes in the pathophysiology of PWS. However, early diagnosis and difficulty in treating some of the disease’s most disabling features remain challenging. As our understanding of PWS continues to grow, so does the availability of new therapies and management strategies available to clinicians and families.
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Isles AR. The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders. Transl Psychiatry 2022; 12:210. [PMID: 35597773 PMCID: PMC9124202 DOI: 10.1038/s41398-022-01972-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 11/15/2022] Open
Abstract
Imprinted genes are a subset of mammalian genes that are subject to germline parent-specific epigenetic modifications leading monoallelic expression. Imprinted gene expression is particularly prevalent in the brain and it is unsurprising that mutations affecting their expression can lead to neurodevelopmental and/or neuropsychiatric disorders in humans. Here I review the evidence for this, detailing key neurodevelopmental disorders linked to imprinted gene clusters on human chromosomes 15q11-q13 and 14q32, highlighting genes and possible regulatory links between these different syndromes. Similarly, rare copy number variant mutations at imprinted clusters also provide strong links between abnormal imprinted gene expression and the predisposition to severe psychiatric illness. In addition to direct links between brain-expressed imprinted genes and neurodevelopmental and/or neuropsychiatric disorders, I outline how imprinted genes that are expressed in another tissue hotspot, the placenta, contribute indirectly to abnormal brain and behaviour. Specifically, altered nutrient provisioning or endocrine signalling by the placenta caused by abnormal expression of imprinted genes may lead to increased prevalence of neurodevelopmental and/or neuropsychiatric problems in both the offspring and the mother.
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Affiliation(s)
- Anthony R. Isles
- grid.5600.30000 0001 0807 5670MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, CF24 4HQ UK
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Ondičová M, Irwin RE, Thursby SJ, Hilman L, Caffrey A, Cassidy T, McLaughlin M, Lees-Murdock DJ, Ward M, Murphy M, Lamers Y, Pentieva K, McNulty H, Walsh CP. Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms. Clin Epigenetics 2022; 14:63. [PMID: 35578268 PMCID: PMC9112484 DOI: 10.1186/s13148-022-01282-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/29/2022] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND We previously showed that continued folic acid (FA) supplementation beyond the first trimester of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years, but the biological mechanism for this effect has remained unclear. Using samples from our randomized controlled trial of folic acid supplementation in second and third trimester (FASSTT), where significant improvements in cognitive and psychosocial performance were demonstrated in children from mothers supplemented in pregnancy with 400 µg/day FA compared with placebo, we examined methylation patterns from cord blood (CB) using the EPIC array which covers approximately 850,000 cytosine-guanine (CG) sites across the genome. Genes showing significant differences were verified using pyrosequencing and mechanistic approaches used in vitro to determine effects on transcription. RESULTS FA supplementation resulted in significant differences in methylation, particularly at brain-related genes. Further analysis showed these genes split into two groups. In one group, which included the CES1 gene, methylation changes at the promoters were important for regulating transcription. We also identified a second group which had a characteristic bimodal profile, with low promoter and high gene body (GB) methylation. In the latter, loss of methylation in the GB is linked to decreases in transcription: this group included the PRKAR1B/HEATR2 genes and the dopamine receptor regulator PDE4C. Overall, methylation in CB also showed good correlation with methylation profiles seen in a published data set of late gestation foetal brain samples. CONCLUSION We show here clear alterations in DNA methylation at specific classes of neurodevelopmental genes in the same cohort of children, born to FA-supplemented mothers, who previously showed improved cognitive and psychosocial performance. Our results show measurable differences at neural genes which are important for transcriptional regulation and add to the supporting evidence for continued FA supplementation throughout later gestation. This trial was registered on 15 May 2013 at www.isrctn.com as ISRCTN19917787.
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Affiliation(s)
- Miroslava Ondičová
- Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, UK
| | - Rachelle E Irwin
- Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, UK
| | - Sara-Jayne Thursby
- Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, UK
- The Johns Hopkins University School of Medicine, Baltimore, USA
| | - Luke Hilman
- Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, UK
| | - Aoife Caffrey
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Tony Cassidy
- Psychology Institute, Ulster University, Coleraine, Northern Ireland, UK
| | - Marian McLaughlin
- Psychology Institute, Ulster University, Coleraine, Northern Ireland, UK
| | - Diane J Lees-Murdock
- Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, UK
| | - Mary Ward
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Michelle Murphy
- Unitat de Medicina Preventiva i Salut Pública, Facultat de Medicina i Ciències de La Salut, Universitat Rovira i Virgili, Reus, Spain
| | - Yvonne Lamers
- Food, Nutrition, and Health Program, Faculty of Land and Food Systems, The University of British Columbia, and British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Kristina Pentieva
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Helene McNulty
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Colum P Walsh
- Genomic Medicine Research Group, Ulster University, Coleraine, Northern Ireland, UK.
- Centre for Research and Development, Region Gävleborg/Uppsala University, Gävle, Sweden.
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Context-Dependent Regulation of Gene Expression by Non-Canonical Small RNAs. Noncoding RNA 2022; 8:ncrna8030029. [PMID: 35645336 PMCID: PMC9149963 DOI: 10.3390/ncrna8030029] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/02/2022] Open
Abstract
In recent functional genomics studies, a large number of non-coding RNAs have been identified. It has become increasingly apparent that noncoding RNAs are crucial players in a wide range of cellular and physiological functions. They have been shown to modulate gene expression on different levels, including transcription, post-transcriptional processing, and translation. This review aims to highlight the diverse mechanisms of the regulation of gene expression by small noncoding RNAs in different conditions and different types of human cells. For this purpose, various cellular functions of microRNAs (miRNAs), circular RNAs (circRNAs), snoRNA-derived small RNAs (sdRNAs) and tRNA-derived fragments (tRFs) will be exemplified, with particular emphasis on the diversity of their occurrence and on the effects on gene expression in different stress conditions and diseased cell types. The synthesis and effect on gene expression of these noncoding RNAs varies in different cell types and may depend on environmental conditions such as different stresses. Moreover, noncoding RNAs play important roles in many diseases, including cancer, neurodegenerative disorders, and viral infections.
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Ning Y, Czekalski M, Herrada S, Greene C. Interpretation challenge of small copy number variations in the imprinting regions. Mol Genet Genomic Med 2022; 10:e1961. [PMID: 35484641 PMCID: PMC9266595 DOI: 10.1002/mgg3.1961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/18/2022] [Indexed: 11/21/2022] Open
Affiliation(s)
- Yi Ning
- Department of PathologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Megan Czekalski
- Department of PediatricsUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Sylvia Herrada
- Department of PediatricsUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Carol Greene
- Department of PediatricsUniversity of Maryland School of MedicineBaltimoreMarylandUSA
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Müller HL, Tauber M, Lawson EA, Özyurt J, Bison B, Martinez-Barbera JP, Puget S, Merchant TE, van Santen HM. Hypothalamic syndrome. Nat Rev Dis Primers 2022; 8:24. [PMID: 35449162 DOI: 10.1038/s41572-022-00351-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/08/2022] [Indexed: 12/11/2022]
Abstract
Hypothalamic syndrome (HS) is a rare disorder caused by disease-related and/or treatment-related injury to the hypothalamus, most commonly associated with rare, non-cancerous parasellar masses, such as craniopharyngiomas, germ cell tumours, gliomas, cysts of Rathke's pouch and Langerhans cell histiocytosis, as well as with genetic neurodevelopmental syndromes, such as Prader-Willi syndrome and septo-optic dysplasia. HS is characterized by intractable weight gain associated with severe morbid obesity, multiple endocrine abnormalities and memory impairment, attention deficit and reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition but treatments for general obesity are often used in patients with HS, including surgery, medication and counselling. However, these are mostly ineffective and no medications that are specifically approved for the treatment of HS are available. Specific challenges in HS are because the syndrome represents an adverse effect of different diseases, and that diagnostic criteria, aetiology, pathogenesis and management of HS are not completely defined.
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Affiliation(s)
- Hermann L Müller
- Department of Paediatrics and Paediatric Hematology/Oncology, University Children's Hospital, Klinikum Oldenburg AöR, Carl von Ossietzky University, Oldenburg, Germany.
| | - Maithé Tauber
- Centre de Référence du Syndrome de Prader-Willi et autres syndromes avec troubles du comportement alimentaire, Hôpital des Enfants, CHU-Toulouse, Toulouse, France
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity) INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France
| | - Elizabeth A Lawson
- Neuroendocrine Unit, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jale Özyurt
- Biological Psychology Laboratory, Department of Psychology, School of Medicine and Health Sciences, Carl von Ossietzky University, Oldenburg, Germany
- Research Center Neurosensory Science, Carl von Ossietzky University, Oldenburg, Germany
| | - Brigitte Bison
- Department of Neuroradiology, University Hospital Augsburg, Augsburg, Germany
| | - Juan-Pedro Martinez-Barbera
- Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Stephanie Puget
- Service de Neurochirurgie, Hôpital Necker-Enfants Malades, Sorbonne Paris Cité, Paris, France
- Service de Neurochirurgie, Hopital Pierre Zobda Quitman, Martinique, France
| | - Thomas E Merchant
- Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hanneke M van Santen
- Department of Paediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands
- Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands
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Baldini L, Robert A, Charpentier B, Labialle S. Phylogenetic and molecular analyses identify SNORD116 targets involved in the Prader Willi syndrome. Mol Biol Evol 2021; 39:6454102. [PMID: 34893870 PMCID: PMC8789076 DOI: 10.1093/molbev/msab348] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The eutherian-specific SNORD116 family of repeated box C/D snoRNA genes is suspected to play a major role in the Prader–Willi syndrome (PWS), yet its molecular function remains poorly understood. Here, we combined phylogenetic and molecular analyses to identify candidate RNA targets. Based on the analysis of several eutherian orthologs, we found evidence of extensive birth-and-death and conversion events during SNORD116 gene history. However, the consequences for phylogenetic conservation were heterogeneous along the gene sequence. The standard snoRNA elements necessary for RNA stability and association with dedicated core proteins were the most conserved, in agreement with the hypothesis that SNORD116 generate genuine snoRNAs. In addition, one of the two antisense elements typically involved in RNA target recognition was largely dominated by a unique sequence present in at least one subset of gene paralogs in most species, likely the result of a selective effect. In agreement with a functional role, this ASE exhibited a hybridization capacity with putative mRNA targets that was strongly conserved in eutherians. Moreover, transient downregulation experiments in human cells showed that Snord116 controls the expression and splicing levels of these mRNAs. The functions of two of them, diacylglycerol kinase kappa and Neuroligin 3, extend the description of the molecular bases of PWS and reveal unexpected molecular links with the Fragile X syndrome and autism spectrum disorders.
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Affiliation(s)
- Laeya Baldini
- Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France
| | - Anne Robert
- Université de Lorraine, CNRS, IMoPA, F-54000 Nancy, France
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Ansell BRE, Thomas SN, Bonelli R, Munro JE, Freytag S, Bahlo M. A survey of RNA editing at single-cell resolution links interneurons to schizophrenia and autism. RNA (NEW YORK, N.Y.) 2021; 27:1482-1496. [PMID: 34535545 PMCID: PMC8594476 DOI: 10.1261/rna.078804.121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 09/12/2021] [Indexed: 06/13/2023]
Abstract
Conversion of adenosine to inosine in RNA by ADAR enzymes, termed "RNA editing," is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been investigated at scale at the level of individual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3' UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including RBFOX1, its target genes, and genes in the autism-associated Prader-Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.
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Affiliation(s)
- Brendan Robert E Ansell
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville 3052, Victoria, Australia
| | - Simon N Thomas
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville 3052, Victoria, Australia
| | - Roberto Bonelli
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville 3052, Victoria, Australia
| | - Jacob E Munro
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville 3052, Victoria, Australia
| | - Saskia Freytag
- Molecular Medicine Division, Harry Perkins Institute of Medical Research, Nedlands 6009, Western Australia, Australia
| | - Melanie Bahlo
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville 3052, Victoria, Australia
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Wang T, Li J, Yang L, Wu M, Ma Q. The Role of Long Non-coding RNAs in Human Imprinting Disorders: Prospective Therapeutic Targets. Front Cell Dev Biol 2021; 9:730014. [PMID: 34760887 PMCID: PMC8573313 DOI: 10.3389/fcell.2021.730014] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/23/2021] [Indexed: 12/26/2022] Open
Abstract
Genomic imprinting is a term used for an intergenerational epigenetic inheritance and involves a subset of genes expressed in a parent-of-origin-dependent way. Imprinted genes are expressed preferentially from either the paternally or maternally inherited allele. Long non-coding RNAs play essential roles in regulating this allele-specific expression. In several well-studied imprinting clusters, long non-coding RNAs have been found to be essential in regulating temporal- and spatial-specific establishment and maintenance of imprinting patterns. Furthermore, recent insights into the epigenetic pathological mechanisms underlying human genomic imprinting disorders suggest that allele-specific expressed imprinted long non-coding RNAs serve as an upstream regulator of the expression of other protein-coding or non-coding imprinted genes in the same cluster. Aberrantly expressed long non-coding RNAs result in bi-allelic expression or silencing of neighboring imprinted genes. Here, we review the emerging roles of long non-coding RNAs in regulating the expression of imprinted genes, especially in human imprinting disorders, and discuss three strategies targeting the central long non-coding RNA UBE3A-ATS for the purpose of developing therapies for the imprinting disorders Prader-Willi syndrome and Angelman syndrome. In summary, a better understanding of long non-coding RNA-related mechanisms is key to the development of potential therapeutic targets for human imprinting disorders.
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Affiliation(s)
- Tingxuan Wang
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jianjian Li
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Liuyi Yang
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Manyin Wu
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Qing Ma
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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49
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Langouët M, Gorka D, Orniacki C, Dupont-Thibert CM, Chung MS, Glatt-Deeley HR, Germain N, Crandall LJ, Cotney JL, Stoddard CE, Lalande M, Chamberlain SJ. Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons. Hum Mol Genet 2021; 29:3285-3295. [PMID: 32977341 DOI: 10.1093/hmg/ddaa210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/15/2020] [Accepted: 08/26/2020] [Indexed: 12/27/2022] Open
Abstract
Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity. This disorder is caused by the absence of paternally expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a Kruppel-associated box-A-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS induced pluripotent stem cells (iPSCs). However, ZNF274 has many other targets in the genome in addition to SNORD116. Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here, we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared with ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116. These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
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Affiliation(s)
- Maéva Langouët
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Dea Gorka
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Clarisse Orniacki
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Clémence M Dupont-Thibert
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Michael S Chung
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Heather R Glatt-Deeley
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Noelle Germain
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Leann J Crandall
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Justin L Cotney
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
| | - Christopher E Stoddard
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Marc Lalande
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
| | - Stormy J Chamberlain
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
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Zhang K, Liu S, Gu W, Lv Y, Yu H, Gao M, Wang D, Zhao J, Li X, Gai Z, Zhao S, Liu Y, Yuan Y. Transmission of a Novel Imprinting Center Deletion Associated With Prader-Willi Syndrome Through Three Generations of a Chinese Family: Case Presentation, Differential Diagnosis, and a Lesson Worth Thinking About. Front Genet 2021; 12:630650. [PMID: 34504512 PMCID: PMC8421676 DOI: 10.3389/fgene.2021.630650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 07/19/2021] [Indexed: 12/02/2022] Open
Abstract
Prader-Willi syndrome (PWS) is a complex genetic syndrome caused by the loss of function of genes in 15q11-q13 that are subject to regulation by genomic imprinting and expressed from the paternal allele only. The main clinical features of PWS patients are hypotonia during the neonatal and infantile stages, accompanied by delayed neuropsychomotor development, hyperphagia, obesity, hypogonadism, short stature, small hands and feet, mental disabilities, and behavioral problems. However, PWS has a clinical overlap with other disorders, especially those with other gene variations or chromosomal imbalances but sharing part of the similar clinical manifestations with PWS, which are sometimes referred to as Prader-Willi syndrome-like (PWS-like) disorders. Furthermore, it is worth mentioning that significant obesity as a consequence of hyperphagia in PWS usually develops between the ages of 1 and 6 years, which makes early diagnosis difficult. Thus, PWS is often not clinically recognized in infants and, on the other hand, may be wrongly suspected in obese and intellectually disabled patients. Therefore, an accurate investigation is necessary to differentiate classical PWS from PWS-like phenotypes, which is imperative for further treatment. For PWS, it is usually sporadic, and very rare family history and affected siblings have been described. Here, we report the clinical and molecular findings in a three-generation family with a novel 550-kb microdeletion affecting the chromosome 15 imprinting center (IC). Overall, the present study finds that the symptoms of our patient are somewhat different from those of typical PWS cases diagnosed and given treatment in our hospital. The familial occurrence and clinical features were challenging to our diagnostic strategy. The microdeletion included a region within the complex small nuclear ribonucleoprotein polypeptide protein N (SNRPN) gene locus encompassing the PWS IC and was identified by using a variety of techniques. Haplotype studies suggest that the IC microdeletion was vertically transmitted from an unaffected paternal grandmother to an unaffected father and then caused PWS in two sibling grandchildren when the IC microdeletion was inherited paternally. Based on the results of our study, preimplantation genetic diagnosis (PGD) was applied successfully to exclude imprinting deficiency in preimplantation embryos before transfer into the mother's uterus. Our study may be especially instructive regarding accurate diagnosis, differential diagnosis, genetic counseling, and PGD for familial PWS patients.
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Affiliation(s)
- Kaihui Zhang
- Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, China
| | - Shu Liu
- Children Inherited Metabolism and Endocrine Department, Guangdong Women and Children Hospital, Guangzhou, China
| | - Wenjun Gu
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, China
| | - Yuqiang Lv
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Haihua Yu
- Neonatal Intensive Care Unit, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Min Gao
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Dong Wang
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Jianyuan Zhao
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, China
| | - Xiaoying Li
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Zhongtao Gai
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Shimin Zhao
- Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, China
- Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yi Liu
- Pediatric Research Institute, Qilu Children’s Hospital of Shandong University, Jinan, China
| | - Yiyuan Yuan
- Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai, China
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