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1
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Kartal D, Dirican MH, Taheri S, Memiş M, Solak EÖ, Cinar SL, Borlu M. Regulation of DNA methylation in lesional tissue of children with atopic dermatitis. Front Med (Lausanne) 2025; 12:1531777. [PMID: 40098928 PMCID: PMC11913172 DOI: 10.3389/fmed.2025.1531777] [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: 11/20/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025] Open
Abstract
Background Genetic and epigenetic mechanisms have been shown to play a role in the pathogenesis of atopic dermatitis (AD). However, the role of genes involved in the establishment of DNA methylation has not yet been demonstrated. Methods A total of 15 pediatric patients with AD and 15 healthy volunteers were included in this study. The mRNA gene expression levels of eight different genes involved in the regulation of DNA methylation were examined in the blood and tissue samples. Results The mRNA expression levels of DNMT3A genes were significantly increased, while the mRNA expression levels of DNMT3B, TET1, and TET2 genes were statistically significantly reduced in the lesional tissue of patients compared to the control group. It was observed that the mRNA expression levels of DNMT1, DNMT3A, and TET3 genes were increased, while the mRNA expression levels of DNMT3L and TET1 genes were found to be decreased in the blood of the patients. Conclusion The results indicated that the DNA methylation pattern in the patients was hypermethylated, especially in the lesional tissue. The data obtained may contribute to the understanding of the epigenetic regulation of AD and aid in the development of new diagnostic and treatment options.
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Affiliation(s)
- Demet Kartal
- Dermatology and Venereology Department, Erciyes University Medical School, Kayseri, Türkiye
| | | | - Serpil Taheri
- Betul Ziya Eren Genome and Stem Cell (GENKÖK) Center, Erciyes University, Kayseri, Türkiye
| | - Mehmet Memiş
- Betul Ziya Eren Genome and Stem Cell (GENKÖK) Center, Erciyes University, Kayseri, Türkiye
- Technology Transfer Office Application and Research Center, Bayburt University, Bayburt, Türkiye
| | - Eda Öksüm Solak
- Dermatology and Venereology Department, Erciyes University Medical School, Kayseri, Türkiye
| | - Salih Levent Cinar
- Dermatology and Venereology Department, Erciyes University Medical School, Kayseri, Türkiye
| | - Murat Borlu
- Dermatology and Venereology Department, Erciyes University Medical School, Kayseri, Türkiye
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2
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Liu Z, Gu A, Bao Y, Lin GN. Epigenetic Impacts of Non-Coding Mutations Deciphered Through Pre-Trained DNA Language Model at Single-Cell Resolution. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413571. [PMID: 39888214 PMCID: PMC11924033 DOI: 10.1002/advs.202413571] [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: 10/24/2024] [Revised: 01/20/2025] [Indexed: 02/01/2025]
Abstract
DNA methylation plays a critical role in gene regulation, affecting cellular differentiation and disease progression, particularly in non-coding regions. However, predicting the epigenetic consequences of non-coding mutations at single-cell resolution remains a challenge. Existing tools have limited prediction capacity and struggle to capture dynamic, cell-type-specific regulatory changes that are crucial for understanding disease mechanisms. Here, Methven, a deep learning framework designed is presented to predict the effects of non-coding mutations on DNA methylation at single-cell resolution. Methven integrates DNA sequence with single-cell ATAC-seq data and models SNP-CpG interactions over 100 kbp genomic distances. By using a divide-and-conquer approach, Methven accurately predicts both short- and long-range regulatory interactions and leverages the pre-trained DNA language model for enhanced precision in classification and regression tasks. Methven outperforms existing methods and demonstrates robust generalizability to monocyte datasets. Importantly, it identifies CpG sites associated with rheumatoid arthritis, revealing key pathways involved in immune regulation and disease progression. Methven's ability to detect progressive epigenetic changes provides crucial insights into gene regulation in complex diseases. These findings demonstrate Methven's potential as a powerful tool for basic research and clinical applications, advancing this understanding of non-coding mutations and their role in disease, while offering new opportunities for personalized medicine.
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Affiliation(s)
- Zhe Liu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200230China
| | - An Gu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200230China
| | - Yihang Bao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200230China
| | - Guan Ning Lin
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai200230China
- Shanghai Key Laboratory of Psychotic DisordersShanghai200230China
- Engineering Research Center of Digital Medicine of the Ministry of EducationShanghai200230China
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3
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Mengistu DY, Terribili M, Pellacani C, Ciapponi L, Marzullo M. Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis. FRONTIERS IN MOLECULAR MEDICINE 2025; 5:1530719. [PMID: 40017539 PMCID: PMC11865237 DOI: 10.3389/fmmed.2025.1530719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/22/2025] [Indexed: 03/01/2025]
Abstract
Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.
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Affiliation(s)
- D. Y. Mengistu
- Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - M. Terribili
- Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - C. Pellacani
- Istituto Di Biologia e Patologia Molecolari, CNR, Sapienza Università Di Roma, Rome, Italy
| | - L. Ciapponi
- Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - M. Marzullo
- Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy
- Istituto Di Biologia e Patologia Molecolari, CNR, Sapienza Università Di Roma, Rome, Italy
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Canton APM, Macedo DB, Abreu AP, Latronico AC. Genetics and Epigenetics of Human Pubertal Timing: The Contribution of Genes Associated With Central Precocious Puberty. J Endocr Soc 2025; 9:bvae228. [PMID: 39839367 PMCID: PMC11746960 DOI: 10.1210/jendso/bvae228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Indexed: 01/23/2025] Open
Abstract
Human puberty is a dynamic biological process determined by the increase in the pulsatile secretion of GnRH triggered by distinct factors not fully understood. Current knowledge reveals fine tuning between an increase in stimulatory factors and a decrease in inhibitory factors, where genetic and epigenetic factors have been indicated as key players in the regulation of puberty onset by distinct lines of evidence. Central precocious puberty (CPP) results from the premature reactivation of pulsatile secretion of GnRH. In the past decade, the identification of genetic causes of CPP has largely expanded, revealing hypothalamic regulatory factors of pubertal timing. Among them, 3 genes associated with CPP are linked to mechanisms involving DNA methylation, reinforcing the strong role of epigenetics underlying this disorder. Loss-of-function mutations in Makorin Ring-Finger Protein 3 (MKRN3) and Delta-Like Non-Canonical Notch Ligand 1 (DLK1), 2 autosomal maternally imprinted genes, have been described as relevant monogenic causes of CPP with the phenotype exclusively associated with paternal transmission. MKRN3 has proven to be a key component of the hypothalamic inhibitory input on GnRH neurons through different mechanisms. Additionally, rare heterozygous variants in the Methyl-CpG-Binding Protein 2 (MECP2), an X-linked gene that is a key factor of DNA methylation machinery, were identified in girls with sporadic CPP with or without neurodevelopmental disorders. In this mini-review, we focus on how the identification of genetic causes of CPP has revealed epigenetic regulators of human pubertal timing, summarizing the latest knowledge on the associations of puberty with MKRN3, DLK1, and MECP2.
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Affiliation(s)
- Ana Pinheiro Machado Canton
- Cellular and Molecular Endocrinology Laboratory LIM/25, Division of Endocrinology and Metabolism, Clinicas Hospital, School of Medicine, University of Sao Paulo, 01246-903 Sao Paulo, Brazil
| | - Delanie Bulcao Macedo
- Integrated Medical Care Center, Center for Health Sciences, University of Fortaleza (Unifor), Fortaleza 60811-905, Brazil
| | - Ana Paula Abreu
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Ana Claudia Latronico
- Cellular and Molecular Endocrinology Laboratory LIM/25, Division of Endocrinology and Metabolism, Clinicas Hospital, School of Medicine, University of Sao Paulo, 01246-903 Sao Paulo, Brazil
- Discipline of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, University of Sao Paulo, 05403-000, Sao Paulo, Brazil
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Wang Q, Ma C, Yang B, Zheng W, Liu X, Jian G. Dysregulation of DNA methylation in colorectal cancer: biomarker, immune regulation, and therapeutic potential. Int Immunopharmacol 2025; 145:113766. [PMID: 39644791 DOI: 10.1016/j.intimp.2024.113766] [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: 11/10/2024] [Revised: 11/16/2024] [Accepted: 11/30/2024] [Indexed: 12/09/2024]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with morbidity and mortality ranking third and second among all cancers, respectively. As a result of a sequence of genetic and DNA methylation alterations that gradually accumulate in the healthy colonic epithelium, colorectal adenomas and invasive adenocarcinomas eventually give rise to CRC. Global hypomethylation and promoter-specific DNA methylation are characteristics of CRC. The pathophysiological role of aberrant DNA methylation in malignant tumors has garnered significant interest in the last few decades. In addition, DNA methylation has been shown to play a critical role in influencing immune cell function and tumor immune evasion. This review summarizes the most recent research on DNA methylation changes in CRC, including the role of DNA methylation-related enzymes in CRC tumorigenesis and biomarkers for diagnosis, predictive and prognostic. Besides, we focus on the emerging potential of epigenetic interventions to enhance antitumor immune responses and improve the CRC clinical practice.
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Affiliation(s)
- Qin Wang
- School of Pharmacy, Southwest Minzu University, Chengdu, China; Department of Pathology, Yong Yoo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Chen Ma
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Bin Yang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenxin Zheng
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Xinya Liu
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Gu Jian
- School of Pharmacy, Southwest Minzu University, Chengdu, China
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Song J, Wu Y, Chen Y, Sun X, Zhang Z. Epigenetic regulatory mechanism of macrophage polarization in diabetic wound healing (Review). Mol Med Rep 2025; 31:2. [PMID: 39422035 PMCID: PMC11551531 DOI: 10.3892/mmr.2024.13367] [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: 07/27/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Diabetic wounds represent a significant complication of diabetes and present a substantial challenge to global public health. Macrophages are crucial effector cells that play a pivotal role in the pathogenesis of diabetic wounds, through their polarization into distinct functional phenotypes. The field of epigenetics has emerged as a rapidly advancing research area, as this phenomenon has the potential to markedly affect gene expression, cellular differentiation, tissue development and susceptibility to disease. Understanding epigenetic mechanisms is crucial to further exploring disease pathogenesis. A growing body of scientific evidence has highlighted the pivotal role of epigenetics in the regulation of macrophage phenotypes. Various epigenetic mechanisms, such as DNA methylation, histone modification and non‑coding RNAs, are involved in the modulation of macrophage phenotype differentiation in response to the various environmental stimuli present in diabetic wounds. The present review provided an overview of the various changes that take place in macrophage phenotypes and functions within diabetic wounds and discussed the emerging role of epigenetic modifications in terms of regulating macrophage plasticity in diabetic wounds. It is hoped that this synthesis of information will facilitate the elucidation of diabetic wound pathogenesis and the identification of potential therapeutic targets.
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Affiliation(s)
- Jielin Song
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300000, P.R. China
| | - Yuqing Wu
- The First Clinical Medical College, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510000, P.R. China
| | - Yunli Chen
- The First Clinical Medical College, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510000, P.R. China
| | - Xu Sun
- Department of Traditional Chinese Medicine Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300000, P.R. China
| | - Zhaohui Zhang
- Department of Traditional Chinese Medicine Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300000, P.R. China
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Wang Q, Jiang Y, Liao W, Zhu P. Comprehensive Pan-cancer Analysis Revealed CASP10 As a Promising Biomarker For Diverse Tumor Types. Int J Immunopathol Pharmacol 2025; 39:3946320251327620. [PMID: 40152300 PMCID: PMC11954456 DOI: 10.1177/03946320251327620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
We aimed to explore the comprehensive cancer landscape of Caspase-10 (CASP10). CASP10, a member of the caspase family, is located at the human chromosome locus 2q33-34. Studies have suggested its potential role in the development of certain cancers. To evaluate CASP10 expression in normal and pan-cancer tissues, we integrated data from The Cancer Genome Atlas (TCGA), GEO, Human Protein Atlas (HPA), and UALCAN databases. The diagnostic and prognostic significance of CASP10 was analyzed using Receiver Operating Characteristic (ROC), Cox regression, and Kaplan-Meier analysis. Correlations of CASP10 with clinical parameters were assessed via the Wilcoxon test, Kruskal-Wallis test, and logistic regression analysis. Genomic variations were explored with cBioPortal, GSCALite database, and UALCAN databases. LinkedOmics database was used to detect the function of CASP10 in pan-cancer. Interactions between CASP10 and the Tumor Immune Microenvironment (TIME) were investigated using TISIDB, TIMER2, and TISCH databases. The GSCALite database was utilized to assess the sensitivity of CASP10 to small-molecule drugs. In addition, Western Blotting (WB) was employed to detect the expression of the CASP10 in our clinical Liver Hepatocellular Carcinoma (LIHC) and Stomach Adenocarcinoma (STAD) cohorts. The transcription and protein expression of CASP10 significantly differ across cancer types, marking it as a biomarker for diagnosis and prognosis. Its expression correlated with certain clinical characteristics such as histological types and Alpha-Fetoprotein (AFP) levels. CASP10 gene exhibited a 2% alteration frequency across pan-cancer patients, with significant SNV and CNV profiles, and decreased methylation levels. CASP10 was closely related to the Nuclear Factor-κappa B (NF-κB), TNF, cell cycle, and JAK-STAT signal pathways. CASP10 showed correlation with immune components in the tumor microenvironment, including lymphocytes, immune stimulators, immune inhibitors, MHC molecules, chemokines, receptors, and Cancer-Associated Fibroblasts (CAFs). Importantly, CASP10 could predict the sensitivity of diverse anti-cancer drugs. Finally, WB analysis validated the overexpression of CASP10 in LIHC and STAD tissues. Our comprehensive bioinformatic analysis reveal the function of CASP10 on the diagnosis, prognosis, and progression of diverse cancer types.
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Affiliation(s)
- Qian Wang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- The Precision Medical Institute, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Yaping Jiang
- Department of Clinical Laboratory, Xi’an NO. 3 Hospital, Xi’an, China
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Pengpeng Zhu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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8
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Rolls W, Wilson MD, Sproul D. Using human disease mutations to understand de novo DNA methyltransferase function. Biochem Soc Trans 2024; 52:2059-2075. [PMID: 39446312 PMCID: PMC11555716 DOI: 10.1042/bst20231017] [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: 07/30/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 11/01/2024]
Abstract
DNA methylation is a repressive epigenetic mark that is pervasive in mammalian genomes. It is deposited by DNA methyltransferase enzymes (DNMTs) that are canonically classified as having de novo (DNMT3A and DNMT3B) or maintenance (DNMT1) function. Mutations in DNMT3A and DNMT3B cause rare Mendelian diseases in humans and are cancer drivers. Mammalian DNMT3 methyltransferase activity is regulated by the non-catalytic region of the proteins which contain multiple chromatin reading domains responsible for DNMT3A and DNMT3B recruitment to the genome. Characterising disease-causing missense mutations has been central in dissecting the function and regulation of DNMT3A and DNMT3B. These observations have also motivated biochemical studies that provide the molecular details as to how human DNMT3A and DNMT3B mutations drive disorders. Here, we review progress in this area highlighting recent work that has begun dissecting the function of the disordered N-terminal regions of DNMT3A and DNMT3B. These studies have elucidated that the N-terminal regions of both proteins mediate novel chromatin recruitment pathways that are central in our understanding of human disease mechanisms. We also discuss how disease mutations affect DNMT3A and DNMT3B oligomerisation, a process that is poorly understood in the context of whole proteins in cells. This dissection of de novo DNMT function using disease-causing mutations provides a paradigm of how genetics and biochemistry can synergise to drive our understanding of the mechanisms through which chromatin misregulation causes human disease.
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Affiliation(s)
- Willow Rolls
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, U.K
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, U.K
| | - Marcus D. Wilson
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, U.K
| | - Duncan Sproul
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, U.K
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, U.K
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Davletgildeeva AT, Kuznetsov NA. Dealkylation of Macromolecules by Eukaryotic α-Ketoglutarate-Dependent Dioxygenases from the AlkB-like Family. Curr Issues Mol Biol 2024; 46:10462-10491. [PMID: 39329974 PMCID: PMC11431407 DOI: 10.3390/cimb46090622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024] Open
Abstract
Alkylating modifications induced by either exogenous chemical agents or endogenous metabolites are some of the main types of damage to DNA, RNA, and proteins in the cell. Although research in recent decades has been almost entirely devoted to the repair of alkyl and in particular methyl DNA damage, more and more data lately suggest that the methylation of RNA bases plays an equally important role in normal functioning and in the development of diseases. Among the most prominent participants in the repair of methylation-induced DNA and RNA damage are human homologs of Escherichia coli AlkB, nonheme Fe(II)/α-ketoglutarate-dependent dioxygenases ABH1-8, and FTO. Moreover, some of these enzymes have been found to act on several protein targets. In this review, we present up-to-date data on specific features of protein structure, substrate specificity, known roles in the organism, and consequences of disfunction of each of the nine human homologs of AlkB. Special attention is given to reports about the effects of natural single-nucleotide polymorphisms on the activity of these enzymes and to potential consequences for carriers of such natural variants.
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Affiliation(s)
- Anastasiia T. Davletgildeeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia;
| | - Nikita A. Kuznetsov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia;
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
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Davletgildeeva AT, Kuznetsov NA. The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level. Biomolecules 2024; 14:1117. [PMID: 39334883 PMCID: PMC11430729 DOI: 10.3390/biom14091117] [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: 07/24/2024] [Revised: 08/26/2024] [Accepted: 08/31/2024] [Indexed: 09/30/2024] Open
Abstract
This review deals with the functional characteristics and biological roles of enzymes participating in DNA methylation and demethylation as key factors in epigenetic regulation of gene expression. The set of enzymes that carry out such processes in human cells is limited to representatives of two families, namely DNMT (DNA methyltransferases) and TET (DNA dioxygenases). The review presents detailed information known today about each functionally important member of these families and describes the catalytic activity and roles in the mammalian body while also providing examples of dysregulation of the expression and/or activity of these enzymes in conjunction with the development of some human disorders, including cancers, neurodegenerative diseases, and developmental pathologies. By combining the up-to-date information on the dysfunction of various enzymes that control the DNA "methylome" in the human body, we hope not only to draw attention to the importance of the maintenance of a required DNA methylation level (ensuring epigenetic regulation of gene expression and normal functioning of the entire body) but also to help identify new targets for directed control over the activity of the enzymes that implement the balance between processes of DNA methylation and demethylation.
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Affiliation(s)
- Anastasiia T Davletgildeeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Nikita A Kuznetsov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
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11
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Xue F, Liu L, Tao X, Zhu W. TET3-mediated DNA demethylation modification activates SHP2 expression to promote endometrial cancer progression through the EGFR/ERK pathway. J Gynecol Oncol 2024; 35:e64. [PMID: 38456588 PMCID: PMC11390245 DOI: 10.3802/jgo.2024.35.e64] [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: 09/08/2023] [Revised: 12/18/2023] [Accepted: 02/11/2024] [Indexed: 03/09/2024] Open
Abstract
OBJECTIVE Src homology phosphotyrosin phosphatase 2 (SHP2) has been implicated in the progression of several cancer types. However, its function in endometrial cancer (EC) remains unclear. Here, we report that the ten-eleven translocation 3 (TET3)-mediated DNA demethylation modification is responsible for the oncogenic role of SHP2 in EC and explore the detailed mechanism. METHODS The transcriptomic differences between EC tissues and control tissues were analyzed using bioinformatics tools, followed by protein-protein interaction network establishment. EC cells were treated with shRNA targeting SHP2 alone or in combination with isoprocurcumenol, an epidermal growth factor receptor (EGFR) signaling activator. The cell biological behavior was examined using cell counting kit-8, colony formation, flow cytometry, scratch assay, and transwell assays, and the median inhibition concentration values to medroxyprogesterone acetate/gefitinib were calculated. The binding of TET3 to the SHP2 promoter was verified. EC cells with TET3 knockdown and combined with SHP2 overexpression were selected to construct tumor xenografts in mice. RESULTS TET3 and SHP2 were overexpressed in EC cells. TET3 bound to the SHP2 promoter, thereby increasing the DNA hydroxymethylation modification and activating SHP2 to induce the EGFR/extracellular signal-regulated kinase (ERK) pathway. Knockdown of TET3 or SHP2 inhibited EC cell malignant aggressiveness and impaired the EGFR/ERK pathway. Silencing of TET3 inhibited the tumorigenic capacity of EC cells, and ectopic expression of SHP2 or isoprocurcumenol reversed the inhibitory effect of TET3 knockdown on the biological activity of EC cells. CONCLUSION TET3 promoted the DNA demethylation modification in the SHP2 promoter and activated SHP2, thus activating the EGFR/ERK pathway and leading to EC progression.
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Affiliation(s)
- Fen Xue
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Obstetrics and Gynecology, The Fourth Hospital of Baotou, Baotou, China
| | - Lifen Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueqiang Tao
- Department of Spinal Surgery, The Fourth Hospital of Baotou, Baotou, China
| | - Weipei Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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Shi Y, Huang R, Zhang Y, Feng Q, Pan X, Wang L. RNA Interference Induces BRCA1 Gene Methylation and Increases the Radiosensitivity of Breast Cancer Cells. Cancer Biother Radiopharm 2024; 39:406-424. [PMID: 35180362 DOI: 10.1089/cbr.2021.0346] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose: To investigate the relationship between breast cancer susceptibility gene-1 (BRCA1) gene methylation and the radiosensitivity of breast cancer. Materials and Methods: The authors studied three breast cancer cell lines: MDA-MB-435, MDA-MB-231, and MCF-7 cells. They constructed five short hairpin RNAs (shRNAs) and five small interfering RNAs to target selected promoter loci and initiate sequence-specific methylation in breast cancer cells. Pyrosequencing was used to analyze the state of DNA methylation. Quantitative real-time polymerase chain reaction was used to detect BRCA1 mRNA expression and RNA-directed DNA methylation (RdDM)-related gene expression. Western blotting was performed to analyze BRCA1 protein expression. Colony formation assays and γ-histone H2A foci formation assays were conducted to assess the surviving fraction (SF) and double-strand break (DSB) repair ability of cells after irradiation. Results: The authors constructed five strains of lentivirus vectors and five plasmid vectors targeting BRCA1 promoter region. In MDA-MB-435 cells, lentivirus-mediated RNA interference targeting Site 1 of BRCA1 increased the methylation levels of BRCA1 and reduced BRCA1 mRNA and protein expression. The SF and the ability to repair DNA DSBs were reduced in the combined LV-BRCA1RNAi-Site 1 infection and irradiation group. Conclusions: The authors' findings suggest that the shRNA suppressed the expression levels of the BRCA1 gene and reduced the SF and DNA repair ability of cells after irradiation through RdDM. In summary, the radiosensitivity of breast cancer cells may correlate with BRCA1 methylation. Advances in Knowledge: The authors first utilized a lentivirus-based shRNA-mediated specific-sequence DNA methylation of the BRCA1 gene mediated by RdDM.
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Affiliation(s)
- Yuebin Shi
- Department of Pathology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Rui Huang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Qiang Feng
- Department of Pathology, 920th Hospital of Joint Logistics Support Force of PLA, Kunming, Yunnan, China
| | - Xinyan Pan
- Department of Pathology, 920th Hospital of Joint Logistics Support Force of PLA, Kunming, Yunnan, China
| | - Li Wang
- Department of Pathology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
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Fialková V, Ďúranová H, Borotová P, Klongová L, Grabacka M, Speváková I. Natural Stilbenes: Their Role in Colorectal Cancer Prevention, DNA Methylation, and Therapy. Nutr Cancer 2024; 76:760-788. [PMID: 38950568 DOI: 10.1080/01635581.2024.2364391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 07/03/2024]
Abstract
The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects, significantly limits effective anticancer strategies. Numerous epigenetic investigations have unveiled that naturally occurring stilbenes can modify or reverse abnormal epigenetic alterations, particularly aberrant DNA methylation status, offering potential avenues for preventing or treating CRC. By modulating the activity of the DNA methylation machinery components, phytochemicals may influence the various stages of CRC carcinogenesis through multiple molecular mechanisms. Several epigenetic studies, especially preclinical research, have highlighted the effective DNA methylation modulatory effects of stilbenes with minimal adverse effects on organisms, particularly in combination therapies for CRC. However, the available preclinical and clinical data regarding the effects of commonly encountered stilbenes against CRC are currently limited. Therefore, additional epigenetic research is warranted to explore the preventive potential of these phytochemicals in CRC development and to validate their therapeutic application in the prevention and treatment of CRC. This review aims to provide an overview of selected bioactive stilbenes as potential chemopreventive agents for CRC with a focus on their modulatory mechanisms of action, especially in targeting alterations in DNA methylation machinery in CRC.
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Affiliation(s)
- Veronika Fialková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Hana Ďúranová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Petra Borotová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Lucia Klongová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Maja Grabacka
- Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture, Cracow, Poland
| | - Ivana Speváková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
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14
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Cardoso C, Pestana D, Gokuladhas S, Marreiros AD, O'Sullivan JM, Binnie A, TFernandes M, Castelo-Branco P. Identification of Novel DNA Methylation Prognostic Biomarkers for AML With Normal Cytogenetics. JCO Clin Cancer Inform 2024; 8:e2300265. [PMID: 39052947 PMCID: PMC11371081 DOI: 10.1200/cci.23.00265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/08/2024] [Accepted: 05/28/2024] [Indexed: 07/27/2024] Open
Abstract
PURPOSE AML is a hematologic cancer that is clinically heterogeneous, with a wide range of clinical outcomes. DNA methylation changes are a hallmark of AML but are not routinely used as a criterion for risk stratification. The aim of this study was to explore DNA methylation markers that could risk stratify patients with cytogenetically normal AML (CN-AML), currently classified as intermediate-risk. MATERIALS AND METHODS DNA methylation profiles in whole blood samples from 77 patients with CN-AML in The Cancer Genome Atlas (LAML cohort) were analyzed. Individual 5'-cytosine-phosphate-guanine-3' (CpG) sites were assessed for their ability to predict overall survival. The output was validated using DNA methylation profiles from bone marrow samples of 79 patients with CN-AML in a separate data set from the Gene Expression Omnibus. RESULTS In the training set, using DNA methylation data derived from the 450K array, we identified 2,549 CpG sites that could potentially distinguish patients with CN-AML with an adverse prognosis (intermediate-poor) from those with a more favorable prognosis (intermediate-favorable) independent of age. Of these, 25 CpGs showed consistent prognostic potential across both the 450K and 27K array platforms. In a separate validation data set, nine of these 25 CpGs exhibited statistically significant differences in 2-year survival. These nine validated CpGs formed the basis for a combined prognostic biomarker panel, which includes an 8-CpG Somatic Panel and the methylation status of cg23947872. This panel displayed strong predictive ability for 2-year survival, 2-year progression-free survival, and complete remission in the validation cohort. CONCLUSION This study highlights DNA methylation profiling as a promising approach to enhance risk stratification in patients with CN-AML, potentially offering a pathway to more personalized treatment strategies.
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Affiliation(s)
- Cândida Cardoso
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve/Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
| | - Daniel Pestana
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve/Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
| | | | - Ana D. Marreiros
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve/Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
| | - Justin M. O'Sullivan
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve/Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
- Australian Parkinson's Mission, Garvan Institute of Medical Research, Sydney, NSW, Australia
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Alexandra Binnie
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve/Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
- Department of Critical Care, William Osler Health System, Etobicoke, ON, Canada
| | - Mónica TFernandes
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
- School of Health, Universidade do Algarve, Faro, Portugal
| | - Pedro Castelo-Branco
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve/Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, Lisbon, Portugal
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Cai H, Li X, Liu Y, Ke J, Liu K, Xie Y, Xie C, Zhou D, Han M, Ji B. Decitabine-based nanoparticles for enhanced immunotherapy of hepatocellular carcinoma via DNA hypermethylation reversal. CHEMICAL ENGINEERING JOURNAL 2024; 492:152175. [DOI: 10.1016/j.cej.2024.152175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/05/2024]
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16
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Shen H, Chen Y, Xu M, Zhou J, Huang C, Wang Z, Shao Y, Zhang H, Lu Y, Li S, Fu Z. Cellular senescence gene TACC3 associated with colorectal cancer risk via genetic and DNA methylated alteration. Arch Toxicol 2024; 98:1499-1513. [PMID: 38480537 DOI: 10.1007/s00204-024-03702-9] [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: 11/19/2023] [Accepted: 02/06/2024] [Indexed: 03/27/2024]
Abstract
Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-β-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P = 3.22 × 10-4). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high-TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.
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Affiliation(s)
- Hengyang Shen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yang Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Menghuan Xu
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jieyu Zhou
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Changzhi Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhenling Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Shao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongqiang Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yunfei Lu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shuwei Li
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Zan Fu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
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Shi J, Wang Z, Wang Z, Shao G, Li X. Epigenetic regulation in adult neural stem cells. Front Cell Dev Biol 2024; 12:1331074. [PMID: 38357000 PMCID: PMC10864612 DOI: 10.3389/fcell.2024.1331074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024] Open
Abstract
Neural stem cells (NSCs) exhibit self-renewing and multipotential properties. Adult NSCs are located in two neurogenic regions of adult brain: the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Maintenance and differentiation of adult NSCs are regulated by both intrinsic and extrinsic signals that may be integrated through expression of some key factors in the adult NSCs. A number of transcription factors have been shown to play essential roles in transcriptional regulation of NSC cell fate transitions in the adult brain. Epigenetic regulators have also emerged as key players in regulation of NSCs, neural progenitor cells and their differentiated progeny via epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling and RNA-mediated transcriptional regulation. This minireview is primarily focused on epigenetic regulations of adult NSCs during adult neurogenesis, in conjunction with transcriptional regulation in these processes.
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Affiliation(s)
- Jiajia Shi
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Zilin Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Zhijun Wang
- Zhenhai Lianhua Hospital, Ningbo City, Zhejiang, China
| | - Guofeng Shao
- Department of Cardiothoracic Surgery, Lihuili Hospital Affiliated to Ningbo University, Ningbo City, Zhejiang, China
| | - Xiajun Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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18
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Feng Q, Duan H, Zhou X, Wang Y, Zhang J, Zhang H, Chen G, Bao X. DNA Methyltransferase 3A: A Significant Target for the Discovery of Inhibitors as Potent Anticancer Drugs. Mini Rev Med Chem 2024; 24:507-520. [PMID: 37642180 DOI: 10.2174/1389557523666230825100246] [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: 04/20/2023] [Revised: 06/27/2023] [Accepted: 07/18/2023] [Indexed: 08/31/2023]
Abstract
DNA methyltransferase (DNMT) is a conserved family of Cytosine methylases, which plays a crucial role in the regulation of Epigenetics. They have been considered promising therapeutic targets for cancer. Among the DNMT family, mutations in the DNMT3A subtype are particularly important in hematologic malignancies. The development of specific DNMT3A subtype inhibitors to validate the therapeutic potential of DNMT3A in certain diseases is a significant task. In this review, we summarized the small molecule inhibitors of DNMT3A discovered in recent years and their inhibitory activities, and classified them based on their inhibitory mechanisms.
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Affiliation(s)
- Qixun Feng
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Honggao Duan
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Xinglong Zhou
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Yuning Wang
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Jinda Zhang
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Haoge Zhang
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Guoliang Chen
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Xuefei Bao
- Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
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Hazrati P, Mirtaleb MH, Boroojeni HSH, Koma AAY, Nokhbatolfoghahaei H. Current Trends, Advances, and Challenges of Tissue Engineering-Based Approaches of Tooth Regeneration: A Review of the Literature. Curr Stem Cell Res Ther 2024; 19:473-496. [PMID: 35984017 DOI: 10.2174/1574888x17666220818103228] [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: 04/05/2022] [Revised: 05/17/2022] [Accepted: 06/01/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Tooth loss is a significant health issue. Currently, this situation is often treated with the use of synthetic materials such as implants and prostheses. However, these treatment modalities do not fully meet patients' biological and mechanical needs and have limited longevity. Regenerative medicine focuses on the restoration of patients' natural tissues via tissue engineering techniques instead of rehabilitating with artificial appliances. Therefore, a tissue-engineered tooth regeneration strategy seems like a promising option to treat tooth loss. OBJECTIVE This review aims to demonstrate recent advances in tooth regeneration strategies and discoveries about underlying mechanisms and pathways of tooth formation. RESULTS AND DISCUSSION Whole tooth regeneration, tooth root formation, and dentin-pulp organoid generation have been achieved by using different seed cells and various materials for scaffold production. Bioactive agents are critical elements for the induction of cells into odontoblast or ameloblast lineage. Some substantial pathways enrolled in tooth development have been figured out, helping researchers design their experiments more effectively and aligned with the natural process of tooth formation. CONCLUSION According to current knowledge, tooth regeneration is possible in case of proper selection of stem cells, appropriate design and manufacturing of a biocompatible scaffold, and meticulous application of bioactive agents for odontogenic induction. Understanding innate odontogenesis pathways play a crucial role in accurately planning regenerative therapeutic interventions in order to reproduce teeth.
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Affiliation(s)
- Parham Hazrati
- School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Helia Sadat Haeri Boroojeni
- Oral and Maxillofacial Surgery Department, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hanieh Nokhbatolfoghahaei
- Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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20
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Vatanmakanian M, Steffan JJ, Koul S, Ochoa AC, Chaturvedi LS, Koul HK. Regulation of SPDEF expression by DNA methylation in advanced prostate cancer. Front Endocrinol (Lausanne) 2023; 14:1156120. [PMID: 37900138 PMCID: PMC10600024 DOI: 10.3389/fendo.2023.1156120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 09/13/2023] [Indexed: 10/31/2023] Open
Abstract
Introduction Prostate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to metastatic castration resistant PCa (mCRPC). Moreover, African American men experience disproportionately high mortality rates due to PCa. This study delves into the pivotal role of SPDEF, a prostate specific Ets transcription factor, and its regulation by DNA methylation in the context of PCa progression. Methods We performed Epigenetic reprogramming using daily treatment with non-toxic dose of 5Aza-2-deoxycytidine (5Aza-dC) for two weeks to assess its impact on PDEF expression in prostate cancer cells. Next, we conducted functional studies on reprogrammed cells, including cell migration (wound-healing assay), invasion (Boyden-Chamber test), and proliferation (MTT assay) to comprehensively evaluate the consequences of altered PDEF expression. We used bisulfite sequencing (BSP) to examine DNA methylation at SPDEF promoter. Simultaneously, we utilized siRNA-mediated targeting of key DNMTs (DNMT1, DNMT3A, and DNMT3B) to elucidate their specific role in regulating PDEF. We measured mRNA and protein expressions using qRT-PCR and immune-blotting techniques, respectively. Results In this report, we observed that: a) there is a gradual decrease in SPDEF expression with a concomitant increase in methylated CpG sites within the SPDEF gene during prostate cancer progression from lower to higher Gleason grade; b) Expression of DNMT's (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is an inverse correlation between SPDEF and DNMT expression; c) SPDEF levels are decreased in RC77/T, a line of PCa cells from African American origin similar to PC3 and DU145 cells (CRPC cells), as compared to LNCaP cells , a line of androgen dependent cells,; d) the 5' CpG island of SPDEF gene are hypermethylated in SPDEF-negative CRPC ( PC3, DU145 and RC77/T) cell lines but the same regions are hypomethylated in SPDEF-positive castrate sensitive (LNCaP) cell line ; (e) expression of SPDEF in PCa cells lacking SPDEF decreases cell migration and invasion, but has no significant effect on cell proliferation, and; (f) treatment with the demethylating agent, 5-aza-2'-deoxycytidine, or silencing of the DNMT's by siRNA, partially restores SPDEF expression in SPDEF-negative PCa cell lines, and decreases cell migration and invasion. Discussion These results indicate hypermethylation is a prevalent mechanism for decreasing SPDEF expression during prostate cancer progression. The data demonstrate that loss of SPDEF expression in prostate cancer cells, a critical step in cellular plasticity, results from a potentially reversible process of aberrant DNA methylation. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer.
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Affiliation(s)
- Mousa Vatanmakanian
- Department of Biochemistry & Molecular Biology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- LSU-LCMC (Louisiana Children's Medical Center) Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Joshua J. Steffan
- Program in Urosciences, Division of Urology, Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Sweaty Koul
- LSU-LCMC (Louisiana Children's Medical Center) Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Urology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Augusto C. Ochoa
- Department of Biochemistry & Molecular Biology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- LSU-LCMC (Louisiana Children's Medical Center) Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Lakshmi S. Chaturvedi
- LSU-LCMC (Louisiana Children's Medical Center) Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Urology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Hari K. Koul
- Department of Biochemistry & Molecular Biology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- LSU-LCMC (Louisiana Children's Medical Center) Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Urology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Southeast Louisiana Veterans Health Care System, New Orleans, LA, United States
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Manou M, Loupis T, Vrachnos DM, Katsoulas N, Theocharis S, Kanakoglou DS, Basdra EK, Piperi C, Papavassiliou AG. Enhanced Transcriptional Signature and Expression of Histone-Modifying Enzymes in Salivary Gland Tumors. Cells 2023; 12:2437. [PMID: 37887281 PMCID: PMC10604940 DOI: 10.3390/cells12202437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Salivary gland tumors (SGTs) are rare and complex neoplasms characterized by heterogenous histology and clinical behavior as well as resistance to systemic therapy. Tumor etiology is currently under elucidation and an interplay of genetic and epigenetic changes has been proposed to contribute to tumor development. In this work, we investigated epigenetic regulators and histone-modifying factors that may alter gene expression and participate in the pathogenesis of SGT neoplasms. We performed a detailed bioinformatic analysis on a publicly available RNA-seq dataset of 94 ACC tissues supplemented with clinical data and respective controls and generated a protein-protein interaction (PPI) network of chromatin and histone modification factors. A significant upregulation of TP53 and histone-modifying enzymes SUV39H1, EZH2, PRMT1, HDAC8, and KDM5B, along with the upregulation of DNA methyltransferase DNMT3A and ubiquitin ligase UHRF1 mRNA levels, as well as a downregulation of lysine acetyltransferase KAT2B levels, were detected in ACC tissues. The protein expression of p53, SUV39H1, EZH2, and HDAC8 was further validated in SGT tissues along with their functional deposition of the repressive histone marks H3K9me3 and H3K27me3, respectively. Overall, this study is the first to detect a network of interacting proteins affecting chromatin structure and histone modifications in salivary gland tumor cells, further providing mechanistic insights in the molecular profile of SGTs that confer to altered gene expression programs.
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Affiliation(s)
- Maria Manou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.); (E.K.B.)
| | - Theodoros Loupis
- Haematology Research Laboratory, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; (T.L.); (D.M.V.)
| | - Dimitrios M. Vrachnos
- Haematology Research Laboratory, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; (T.L.); (D.M.V.)
| | - Nikolaos Katsoulas
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (S.T.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (S.T.)
| | - Dimitrios S. Kanakoglou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.); (E.K.B.)
| | - Efthimia K. Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.); (E.K.B.)
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.); (E.K.B.)
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.K.); (E.K.B.)
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22
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Kaplánek R, Kejík Z, Hajduch J, Veselá K, Kučnirová K, Skaličková M, Venhauerová A, Hosnedlová B, Hromádka R, Dytrych P, Novotný P, Abramenko N, Antonyová V, Hoskovec D, Babula P, Masařík M, Martásek P, Jakubek M. TET protein inhibitors: Potential and limitations. Biomed Pharmacother 2023; 166:115324. [PMID: 37598475 DOI: 10.1016/j.biopha.2023.115324] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/31/2023] [Accepted: 08/10/2023] [Indexed: 08/22/2023] Open
Abstract
TET proteins (methylcytosine dioxygenases) play an important role in the regulation of gene expression. Dysregulation of their activity is associated with many serious pathogenic states such as oncological diseases. Regulation of their activity by specific inhibitors could represent a promising therapeutic strategy. Therefore, this review describes various types of TET protein inhibitors in terms of their inhibitory mechanism and possible applicability. The potential and possible limitations of this approach are thoroughly discussed in the context of TET protein functionality in living systems. Furthermore, possible therapeutic strategies based on the inhibition of TET proteins are presented and evaluated, especially in the field of oncological diseases.
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Affiliation(s)
- Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Jan Hajduch
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Kateřina Veselá
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Kateřina Kučnirová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Markéta Skaličková
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Anna Venhauerová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Božena Hosnedlová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Róbert Hromádka
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Petr Dytrych
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121 08 Prague, Czech Republic
| | - Petr Novotný
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Nikita Abramenko
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Veronika Antonyová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - David Hoskovec
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121 08 Prague, Czech Republic
| | - Petr Babula
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Michal Masařík
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Pavel Martásek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic.
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic.
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23
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Shi S, Li J, Zhang Z, Tu H, Max C. Isorhapontigenin (ISO) inhibits malignant cell transformation, migration, and invasion through MEG3/NEDD9 signaling in Cr(VI)-transformed cells. Toxicol Appl Pharmacol 2023; 476:116661. [PMID: 37619952 PMCID: PMC10874125 DOI: 10.1016/j.taap.2023.116661] [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: 07/28/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/26/2023]
Abstract
Cr(VI) compounds are confirmed human carcinogens. Maternally expression 3 (MEG3) is the first long non-coding RNA to be identified as a tumor suppressor. MEG3 is frequently downregulated or lost in various primary human tumor tissues and cancer cell lines. Downregulation of MEG3 is associated with cancer initiation, progression, and metastasis. Our previous study has revealed that MEG3 was lost and NEDD9 was upregulated in Cr(VI)-transformed cells compared to those in passage-matched normal BEAS-2B cells. Overexpression of MEG3 reduced NEDD9. β-Catenin was activated in Cr(VI)-transformed cells, overexpression of MEG3 or knockdown of NEDD9 inhibited the activation of β-Catenin. The results from the present study showed that isorhapontigenin (ISO) treatment is able to suppress cell proliferation, migration, and invasion of Cr(VI)-transformed cells. Further study showed that ISO treatment in Cr(VI)-transformed cells decreases the levels of Ki67, a biomarker for cell proliferation, and of cyclin D1, a regulator for the cell cycle. ISO elevated the MEG3 expression level in Cr(VI)-transformed cells. The DNA methylation transferases DNMT3a, DNMT3b, and DNMT1 levels were reduced upon ISO treatment. ISO treatment decreased both mRNA and protein levels of NEDD9. In addition, ISO treatment reduced the activation of β-catenin. Slug was upregulated and E-Cadherin was downregulated in Cr(VI)-transformed cells, treatment with ISO decreased Slug and increased E-Cadherin. This study demonstrated that ISO is a potent therapeutical agent against lung cancer induced by Cr(VI).
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Affiliation(s)
- Sophia Shi
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Jingxia Li
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Zhuo Zhang
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Huailu Tu
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Costa Max
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America.
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24
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Pessôa R, Clissa PB, Sanabani SS. The Interaction between the Host Genome, Epigenome, and the Gut-Skin Axis Microbiome in Atopic Dermatitis. Int J Mol Sci 2023; 24:14322. [PMID: 37762624 PMCID: PMC10532357 DOI: 10.3390/ijms241814322] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease that occurs in genetically predisposed individuals. It involves complex interactions among the host immune system, environmental factors (such as skin barrier dysfunction), and microbial dysbiosis. Genome-wide association studies (GWAS) have identified AD risk alleles; however, the associated environmental factors remain largely unknown. Recent evidence suggests that altered microbiota composition (dysbiosis) in the skin and gut may contribute to the pathogenesis of AD. Examples of environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, irritants, pollution, and microbial exposure. Studies have reported alterations in the gut microbiome structure in patients with AD compared to control subjects, characterized by increased abundance of Clostridium difficile and decreased abundance of short-chain fatty acid (SCFA)-producing bacteria such as Bifidobacterium. SCFAs play a critical role in maintaining host health, and reduced SCFA production may lead to intestinal inflammation in AD patients. The specific mechanisms through which dysbiotic bacteria and their metabolites interact with the host genome and epigenome to cause autoimmunity in AD are still unknown. By understanding the combination of environmental factors, such as gut microbiota, the genetic and epigenetic determinants that are associated with the development of autoantibodies may help unravel the pathophysiology of the disease. This review aims to elucidate the interactions between the immune system, susceptibility genes, epigenetic factors, and the gut microbiome in the development of AD.
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Affiliation(s)
- Rodrigo Pessôa
- Postgraduate Program in Translational Medicine, Department of Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo 04039-002, Brazil;
| | | | - Sabri Saeed Sanabani
- Laboratory of Medical Investigation LIM-56, Division of Dermatology, Medical School, University of Sao Paulo, Sao Paulo 05508-220, Brazil
- Laboratory of Medical Investigation Unit 03, Clinics Hospital, Faculty of Medicine, University of Sao Paulo, Sao Paulo 05403-000, Brazil
- Laboratory of Dermatology and Immunodeficiency LIM56/03, Instituto de Medicina Tropical de Sao Paulo, Faculdade de Medicina, University of Sao Paulo, Av. Dr. Eneas de Carvalho Aguiar, 470 3º Andar, Sao Paulo 05403-000, Brazil
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25
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Switzer RL, Hartman ZJ, Hewett GR, Carroll CF. Disease-Associated Mutation A554V Disrupts Normal Autoinhibition of DNMT1. DNA 2023; 3:119-133. [PMID: 37663147 PMCID: PMC10470860 DOI: 10.3390/dna3030010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
DNA methyltransferase 1 (DNMT1) is the enzyme primarily responsible for propagation of the methylation pattern in cells. Mutations in DNMT1 have been linked to the development of adult-onset neurodegenerative disorders; these disease-associated mutations occur in the regulatory replication foci-targeting sequence (RFTS) domain of the protein. The RFTS domain is an endogenous inhibitor of DNMT1 activity that binds to the active site and prevents DNA binding. Here, we examine the impact of the disease-associated mutation A554V on normal RFTS-mediated inhibition of DNMT1. Wild-type and mutant proteins were expressed and purified to homogeneity for biochemical characterization. The mutation increased DNA binding affinity ~8-fold. In addition, the mutant enzyme exhibited increased DNA methylation activity. Circular dichroism (CD) spectroscopy revealed that the mutation does not significantly impact the secondary structure or relative thermal stability of the isolated RFTS domain. However, the mutation resulted in changes in the CD spectrum in the context of the larger protein; a decrease in relative thermal stability was also observed. Collectively, this evidence suggests that A554V disrupts normal RFTS-mediated autoinhibition of DNMT1, resulting in a hyperactive mutant enzyme. While the disease-associated mutation does not significantly impact the isolated RFTS domain, the mutation results in a weakening of the interdomain stabilizing interactions generating a more open, active conformation of DNMT1. Hyperactive mutant DNMT1 could be responsible for the increased DNA methylation observed in affected individuals.
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Affiliation(s)
| | - Zach J. Hartman
- Department of Biology, Bucknell University, Lewisburg, PA 17837, USA
| | - Geoffrey R. Hewett
- Program in Cell Biology/Biochemistry, Bucknell University, Lewisburg, PA 17837, USA
| | - Clara F. Carroll
- Department of Chemistry, Bucknell University, Lewisburg, PA 17837, USA
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26
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Hudu SA, Elmigdadi F, Qtaitat AA, Almehmadi M, Alsaiari AA, Allahyani M, Aljuaid A, Salih M, Alghamdi A, Alrofaidi MA, Abida, Imran M. Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need. J Clin Med 2023; 12:5114. [PMID: 37568516 PMCID: PMC10420089 DOI: 10.3390/jcm12155114] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/29/2023] [Accepted: 07/04/2023] [Indexed: 08/13/2023] Open
Abstract
Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.
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Affiliation(s)
- Shuaibu A. Hudu
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Fayig Elmigdadi
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Aiman Al Qtaitat
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
- Department of Anatomy and Histology, Faculty of Medicine, Mutah University, Karak 61710, Jordan
| | - Mazen Almehmadi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ahad Amer Alsaiari
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Mamdouh Allahyani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Abdulelah Aljuaid
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Magdi Salih
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Adel Alghamdi
- Department of Pharmaceutical Chemistry, Faculty of Clinical Pharmacy, Al-Baha University, P.O. Box 1988, Al-Baha 65779, Saudi Arabia
| | - Mohammad A. Alrofaidi
- Department of Pharmaceutical Chemistry, Faculty of Clinical Pharmacy, Al-Baha University, P.O. Box 1988, Al-Baha 65779, Saudi Arabia
| | - Abida
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia;
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia;
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27
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Zhang Z, Guo Q, Zhao Z, Nie M, Shi Q, Li E, Liu K, Yu H, Rao L, Li M. DNMT3B activates FGFR3-mediated endoplasmic reticulum stress by regulating PTPN2 promoter methylation to promote the development of atherosclerosis. FASEB J 2023; 37:e23085. [PMID: 37462502 DOI: 10.1096/fj.202300665r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/19/2023] [Accepted: 06/25/2023] [Indexed: 07/21/2023]
Abstract
Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis (AS). Nevertheless, the regulatory mechanism of ER stress in endothelial cells during AS progression is unclear. Here, the role and regulatory mechanism of DNA (cytosine-5-)- methyltransferase 3 beta (DNMT3B) in ER stress during AS progression were investigated. ApoE-/- mice were fed with high fat diet to construct AS model in vivo. HE and Masson staining were performed to analyze histopathological changes and collagen deposition. HUVECs stimulated by ox-LDL were used as AS cellular model. Cell apoptosis was examined using flow cytometry. DCFH-DA staining was performed to examine ROS level. The levels of pro-inflammatory cytokines were assessed using ELISA. In addition, MSP was employed to detect PTPN2 promoter methylation level. Our results revealed that DNMT3B and FGFR3 were significantly upregulated in AS patient tissues, whereas PTPN2 was downregulated. PTPN2 overexpression attenuate ox-LDL-induced ER stress, inflammation and apoptosis in HUVECs and ameliorated AS symptoms in vivo. PTPN2 could suppress FGFR3 expression in ox-LDL-treated HUVECs, and FGFR3 knockdown inhibited ER stress to attenuate ox-LDL-induced endothelial cell apoptosis. DNMT3B could negatively regulate PTPN2 expression and positively FGFR2 expression in ox-LDL-treated HUVECs; DNMT3B activated FGFR2 expression by increasing PTPN2 promoter methylation level. DNMT3B downregulation repressed ox-LDL-induced ER stress, inflammation and cell apoptosis in endothelial cells, which was reversed by PTPN2 silencing. DNMT3B activated FGFR3-mediated ER stress by increasing PTPN2 promoter methylation level and suppressed its expression, thereby boosting ER stress to facilitate AS progression.
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Affiliation(s)
- Zhiwen Zhang
- Department of Cardiology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Quan Guo
- Department of Cardiology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Zhenzhou Zhao
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Ming Nie
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Qingbo Shi
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - En Li
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Kaiyuan Liu
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Haosen Yu
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Lixin Rao
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
| | - Muwei Li
- Department of Cardiology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Cardiology, Central China Fuwai Hospital, Zhengzhou, China
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28
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Canton APM, Tinano FR, Guasti L, Montenegro LR, Ryan F, Shears D, de Melo ME, Gomes LG, Piana MP, Brauner R, Espino-Aguilar R, Escribano-Muñoz A, Paganoni A, Read JE, Korbonits M, Seraphim CE, Costa SS, Krepischi AC, Jorge AAL, David A, Kaisinger LR, Ong KK, Perry JRB, Abreu AP, Kaiser UB, Argente J, Mendonca BB, Brito VN, Howard SR, Latronico AC. Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study. Lancet Diabetes Endocrinol 2023; 11:545-554. [PMID: 37385287 PMCID: PMC7615084 DOI: 10.1016/s2213-8587(23)00131-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 04/22/2023] [Accepted: 04/22/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.
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Affiliation(s)
- Ana P M Canton
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | - Flávia R Tinano
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | - Leonardo Guasti
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Luciana R Montenegro
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | - Fiona Ryan
- Oxford Children's Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Deborah Shears
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Larissa G Gomes
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Raja Brauner
- Fondation Ophtalmologique Adolphe de Rothschild and Université de Paris, Paris, France
| | | | - Arancha Escribano-Muñoz
- Endocrinology Unit, Department of Pediatrics, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - Alyssa Paganoni
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jordan E Read
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Carlos E Seraphim
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | - Silvia S Costa
- Discipline of Endocrinology and Metabolism, Clinicas Hospital, School of Medicine and Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana Cristina Krepischi
- Discipline of Endocrinology and Metabolism, Clinicas Hospital, School of Medicine and Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Alexander A L Jorge
- Genetic Endocrinology Unit LIM/25, University of Sao Paulo, Sao Paulo, Brazil
| | - Alessia David
- Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, UK
| | - Lena R Kaisinger
- Medical Research Council Epidemiology Unit, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Ken K Ong
- Medical Research Council Epidemiology Unit, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - John R B Perry
- Medical Research Council Epidemiology Unit, Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Ana Paula Abreu
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ursula B Kaiser
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Jesús Argente
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain; Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, IMDEA Food Institute, Madrid, Spain
| | - Berenice B Mendonca
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | - Vinicius N Brito
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil
| | - Sasha R Howard
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK
| | - Ana Claudia Latronico
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, University of Sao Paulo, Sao Paulo, Brazil.
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Li L, Liu Y, Gao F, Fan P, Zhan W, Zhang S. Induced PSIG expression by Herbacetin contributes to suppressing the proliferation, migration, and invasion of melanoma cells. Arch Biochem Biophys 2023:109697. [PMID: 37481197 DOI: 10.1016/j.abb.2023.109697] [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: 02/15/2023] [Revised: 07/11/2023] [Accepted: 07/20/2023] [Indexed: 07/24/2023]
Abstract
Melanoma is a very common malignant tumor with poor prognosis. Herbacetin is a flavonol compound with outstanding anti-tumor effects. Our work investigated the biological effects and mechanism of Herbacetin in melanoma. In our study, the mRNA and protein expressions were assessed using qRT-PCR, Western blot and IHC. MSP was performed to evaluated PGIS promoter methylation level. Cell viability, migration and invasion were examined by MTT assay, transwell migration and invasion assay, respectively. Our results revealed that DNMT3B was markedly upregulated in melanoma, while PGIS was lowly expressed. Herbacetin treatment could not only inhibit the proliferation, migration, invasion of melanoma cells and inhibit the growth of melanoma in vivo. Herbacetin could also restore the abnormal expressions of DNMT3B and PGIS in melanoma cells and tumor tissues. PGIS silencing neutralized the inhibitory effects of Herbacetin on the malignant behaviors of melanoma cells. Besides, DNMT3B knockdown promoted PGIS expression via reducing PGIS promoter methylation level in melanoma cells, thereby inhibiting malignant behaviors of melanoma cells. And as expected, the inhibitory effects of Herbacetin on malignant behaviors of melanoma cells were all abolished by DNMT3B overexpression. Collectively, Herbacetin reduced DNMT3B expression to upregulate PGIS in melanoma cells and participated in suppressing the proliferation, migration, and invasion of melanoma cells.
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Affiliation(s)
- Lei Li
- Department of Plastic abd Cosmetic Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Yun Liu
- Department of Plastic abd Cosmetic Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Fei Gao
- Department of Plastic abd Cosmetic Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Pengfei Fan
- Department of Plastic abd Cosmetic Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Wang Zhan
- Department of Plastic abd Cosmetic Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Shuai Zhang
- Nursing Department, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan Province, PR China.
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Lesta A, Marín-García PJ, Llobat L. How Does Nutrition Affect the Epigenetic Changes in Dairy Cows? Animals (Basel) 2023; 13:1883. [PMID: 37889793 PMCID: PMC10251833 DOI: 10.3390/ani13111883] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 05/25/2023] [Accepted: 06/01/2023] [Indexed: 10/29/2023] Open
Abstract
Dairy cows require a balanced diet that provides enough nutrients to support milk production, growth, and reproduction. Inadequate nutrition can lead to metabolic disorders, impaired fertility, and reduced milk yield. Recent studies have shown that nutrition can affect epigenetic modifications in dairy cows, which can impact gene expression and affect the cows' health and productivity. One of the most important epigenetic modifications in dairy cows is DNA methylation, which involves the addition of a methyl group to the DNA molecule. Studies have shown that the methylation status of certain genes in dairy cows can be influenced by dietary factors such as the level of methionine, lysine, choline, and folate in the diet. Other important epigenetic modifications in dairy cows are histone modification and microRNAs as regulators of gene expression. Overall, these findings suggest that nutrition can have a significant impact on the epigenetic regulation of gene expression in dairy cows. By optimizing the diet of dairy cows, it may be possible to improve their health and productivity by promoting beneficial epigenetic modifications. This paper reviews the main nutrients that can cause epigenetic changes in dairy cattle by analyzing the effect of diet on milk production and its composition.
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Affiliation(s)
- Ana Lesta
- MMOPS Research Group, Departamento Producción y Sanidad Animal, Salud Pública y Ciencia y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Cardenal Herrera—CEU, CEU Universities, 46115 Valencia, Spain;
| | - Pablo Jesús Marín-García
- Department of Animal Production and Health, Veterinary Public Health and Food Science and Technology (PASAPTA), Facultad de Veterinaria, Universidad Cardenal Herrera—CEU, CEU Universities, 46113 Valencia, Spain;
| | - Lola Llobat
- MMOPS Research Group, Departamento Producción y Sanidad Animal, Salud Pública y Ciencia y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Cardenal Herrera—CEU, CEU Universities, 46115 Valencia, Spain;
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31
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Martin S, Poppe D, Olova N, O'Leary C, Ivanova E, Pflueger J, Dechka J, Simmons RK, Cooper HM, Reik W, Lister R, Wolvetang EJ. Embryonic Stem Cell-Derived Neurons as a Model System for Epigenome Maturation during Development. Genes (Basel) 2023; 14:genes14050957. [PMID: 37239317 DOI: 10.3390/genes14050957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 05/28/2023] Open
Abstract
DNA methylation in neurons is directly linked to neuronal genome regulation and maturation. Unlike other tissues, vertebrate neurons accumulate high levels of atypical DNA methylation in the CH sequence context (mCH) during early postnatal brain development. Here, we investigate to what extent neurons derived in vitro from both mouse and human pluripotent stem cells recapitulate in vivo DNA methylation patterns. While human ESC-derived neurons did not accumulate mCH in either 2D culture or 3D organoid models even after prolonged culture, cortical neurons derived from mouse ESCs acquired in vivo levels of mCH over a similar time period in both primary neuron cultures and in vivo development. mESC-derived neuron mCH deposition was coincident with a transient increase in Dnmt3a, preceded by the postmitotic marker Rbfox3 (NeuN), was enriched at the nuclear lamina, and negatively correlated with gene expression. We further found that methylation patterning subtly differed between in vitro mES-derived and in vivo neurons, suggesting the involvement of additional noncell autonomous processes. Our findings show that mouse ESC-derived neurons, in contrast to those of humans, can recapitulate the unique DNA methylation landscape of adult neurons in vitro over experimentally tractable timeframes, which allows their use as a model system to study epigenome maturation over development.
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Affiliation(s)
- Sally Martin
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Daniel Poppe
- Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
| | - Nelly Olova
- Epigenetics ISP, The Babraham Institute, Cambridge CB22 3AT, UK
| | - Conor O'Leary
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Elena Ivanova
- Epigenetics ISP, The Babraham Institute, Cambridge CB22 3AT, UK
| | - Jahnvi Pflueger
- Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
| | - Jennifer Dechka
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Rebecca K Simmons
- Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
| | - Helen M Cooper
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Wolf Reik
- Epigenetics ISP, The Babraham Institute, Cambridge CB22 3AT, UK
- The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
| | - Ryan Lister
- Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
| | - Ernst J Wolvetang
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
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Rodrigues D, Monteiro C, Cardoso-Cruz H, Galhardo V. Altered Brain Expression of DNA Methylation and Hydroxymethylation Epigenetic Enzymes in a Rat Model of Neuropathic Pain. Int J Mol Sci 2023; 24:ijms24087305. [PMID: 37108466 PMCID: PMC10138521 DOI: 10.3390/ijms24087305] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies.
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Affiliation(s)
- Diogo Rodrigues
- Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
- i3S/IBMC, Instituto de Investigação e Inovação em Saúde e Instituto de Biologia Molecular e Celular, Pain Neurobiology Group, Universidade do Porto, 4200-135 Porto, Portugal
| | - Clara Monteiro
- Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
- i3S/IBMC, Instituto de Investigação e Inovação em Saúde e Instituto de Biologia Molecular e Celular, Pain Neurobiology Group, Universidade do Porto, 4200-135 Porto, Portugal
| | - Helder Cardoso-Cruz
- Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
- i3S/IBMC, Instituto de Investigação e Inovação em Saúde e Instituto de Biologia Molecular e Celular, Pain Neurobiology Group, Universidade do Porto, 4200-135 Porto, Portugal
| | - Vasco Galhardo
- Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
- i3S/IBMC, Instituto de Investigação e Inovação em Saúde e Instituto de Biologia Molecular e Celular, Pain Neurobiology Group, Universidade do Porto, 4200-135 Porto, Portugal
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Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis. Exp Mol Med 2023; 55:143-157. [PMID: 36609599 PMCID: PMC9898513 DOI: 10.1038/s12276-022-00919-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/17/2022] [Accepted: 11/13/2022] [Indexed: 01/07/2023] Open
Abstract
Dynamic alteration of DNA methylation leads to various human diseases, including nonalcoholic fatty liver disease (NAFLD). Although C-Maf-inducing protein (Cmip) has been reported to be associated with NAFLD, its exact underlying mechanism remains unclear. Here, we aimed to elucidate this mechanism in NAFLD in vitro and in vivo. We first identified alterations in the methylation status of the Cmip intron 1 region in mouse liver tissues with high-fat high-sucrose diet-induced NAFLD. Knockdown of DNA methyltransferase (Dnmt) 1 significantly increased Cmip expression. Chromatin immunoprecipitation assays of AML12 cells treated with oleic and palmitic acid (OPA) revealed that Dnmt1 was dissociated and that methylation of H3K27me3 was significantly decreased in the Cmip intron 1 region. Conversely, the knockdown of Tet methylcytosine dioxygenase 2 (Tet2) decreased Cmip expression. Following OPA treatment, the CCCTC-binding factor (Ctcf) was recruited, and H3K4me3 was significantly hypermethylated. Intravenous Cmip siRNA injection ameliorated NAFLD pathogenic features in ob/ob mice. Additionally, Pparγ and Cd36 expression levels were dramatically decreased in the livers of ob/ob mice administered siCmip, and RNA sequencing revealed that Gbp2 was involved. Gbp2 knockdown also induced a decrease in Pparγ and Cd36 expression, resulting in the abrogation of fatty acid uptake into cells. Our data demonstrate that Cmip and Gbp2 expression levels are enhanced in human liver tissues bearing NAFLD features. We also show that Dnmt1-Trt2/Ctcf-mediated reversible modulation of Cmip methylation regulates the Gbp2-Pparγ-Cd36 signaling pathway, indicating the potential of Cmip as a novel therapeutic target for NAFLD.
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Kunert S, Linhard V, Weirich S, Choudalakis M, Osswald F, Krämer L, Köhler AR, Bröhm A, Wollenhaupt J, Schwalbe H, Jeltsch A. The MECP2-TRD domain interacts with the DNMT3A-ADD domain at the H3-tail binding site. Protein Sci 2023; 32:e4542. [PMID: 36519786 PMCID: PMC9798253 DOI: 10.1002/pro.4542] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/01/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
The DNMT3A DNA methyltransferase and MECP2 methylation reader are highly expressed in neurons. Both proteins interact via their DNMT3A-ADD and MECP2-TRD domains, and the MECP2 interaction regulates the activity and subnuclear localization of DNMT3A. Here, we mapped the interface of both domains using peptide SPOT array binding, protein pull-down, equilibrium peptide binding assays, and structural analyses. The region D529-D531 on the surface of the ADD domain was identified as interaction point with the TRD domain. This includes important residues of the histone H3 N-terminal tail binding site to the ADD domain, explaining why TRD and H3 binding to the ADD domain is competitive. On the TRD domain, residues 214-228 containing K219 and K223 were found to be essential for the ADD interaction. This part represents a folded patch within the otherwise largely disordered TRD domain. A crystal structure analysis of ADD revealed that the identified H3/TDR lysine binding pocket is occupied by an arginine residue from a crystallographic neighbor in the ADD apoprotein structure. Finally, we show that mutations in the interface of ADD and TRD domains disrupt the cellular interaction of both proteins in NIH3T3 cells. In summary, our data show that the H3 peptide binding cleft of the ADD domain also mediates the interaction with the MECP2-TRD domain suggesting that this binding site may have a broader role also in the interaction of DNMT3A with other proteins leading to complex regulation options by competitive and PTM specific binding.
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Affiliation(s)
- Stefan Kunert
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Verena Linhard
- Center for Biomolecular Magnetic Resonance (BMRZ), Institute for Organic Chemistry and Chemical BiologyGoethe UniversityFrankfurtGermany
| | - Sara Weirich
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Michel Choudalakis
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Florian Osswald
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Lisa Krämer
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Anja R. Köhler
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Alexander Bröhm
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
| | - Jan Wollenhaupt
- Macromolecular Crystallography GroupHelmholtz‐Zentrum BerlinBerlinGermany
| | - Harald Schwalbe
- Center for Biomolecular Magnetic Resonance (BMRZ), Institute for Organic Chemistry and Chemical BiologyGoethe UniversityFrankfurtGermany
| | - Albert Jeltsch
- Institute of Biochemistry and Technical BiochemistryUniversity of StuttgartStuttgartGermany
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The R736H cancer mutation in DNMT3A modulates the properties of the FF-subunit interface. Biochimie 2022; 208:66-74. [PMID: 36528185 DOI: 10.1016/j.biochi.2022.12.005] [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: 09/18/2022] [Revised: 11/21/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
The DNMT3A DNA methyltransferase is an important epigenetic enzyme that is frequently mutated in cancers, particularly in AML. The heterozygous R736H mutation in the FF-interface of the tetrameric enzyme is the second most frequently observed DNMT3A cancer mutation, but its pathogenic mechanism is unclear. We show here that R736H leads to a moderate reduction in catalytic activity of 20-40% depending on the substrate, but no changes in CpG specificity, flanking sequence preferences and subnuclear localization. Strikingly, R736H showed a very strong stimulation by DNMT3L and the R736H/DNMT3L complex was 3-fold more active than WT/DNMT3L. Similarly, formation of mixed R736H/DNMT3A WT FF-interfaces led to an increased activity. R736H/DNMT3L and mixed R736H/DNMT3A WT FF-interfaces were less stable than interfaces not involving R736H, suggesting that an increased flexibility of the mixed interfaces stimulates catalytic activity. Our data suggest that aberrant activity of DNMT3A R736H may lead to DNA hypermethylation in cancer cells which could cause changes in gene expression.
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36
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Recillas-Targa F. Cancer Epigenetics: An Overview. Arch Med Res 2022; 53:732-740. [PMID: 36411173 DOI: 10.1016/j.arcmed.2022.11.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/18/2022] [Accepted: 11/03/2022] [Indexed: 11/19/2022]
Abstract
Cancer is a complex disease caused by genetic and epigenetic alterations in the control of cell division. Findings from the field of cancer genomics and epigenomics have increased our understanding of the origin and evolution of tumorigenic processes, greatly advancing our knowledge of the molecular etiology of cancer. Consequently, any contemporary view of cancer research must consider tumorigenesis as a cellular phenomenon that is a result of the interplay between genetic and epigenetic mutations and their interaction with environmental factors, including our microbiome, that influences cellular metabolism and proliferation rates. The integration and better knowledge of these processes will help us to improve diagnosis, prognosis, and future genetic and epigenetic therapies. Here, I present an overview of the epigenetic processes that are affected in cancer and how they contribute to the onset and progression of the disease. Finally, I discuss how the development of sophisticated experimental approaches and computational tools, including novel ways to exploit large data sets, could contribute to the better understanding and treatment of cancer.
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Affiliation(s)
- Félix Recillas-Targa
- Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, México.
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37
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Hirao-Suzuki M. Mechanisms of Cancer Malignancy Elicited by Environmental Chemicals: Analysis Focusing on Cadmium and Bisphenol A. YAKUGAKU ZASSHI 2022; 142:1161-1168. [DOI: 10.1248/yakushi.22-00140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Yogita Mehra, Pragasam Viswanathan. Early Evidence of Global DNA Methylation and Hydroxymethylation Changes in Rat Kidneys Consequent to Hyperoxaluria-Induced Renal Calcium Oxalate Stones. CYTOL GENET+ 2022; 56:458-465. [DOI: 10.3103/s0095452722050085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/27/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022]
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39
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Chen Y, Li J, Xu L, Găman MA, Zou Z. The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting. Cell Death Discov 2022; 8:397. [PMID: 36163119 PMCID: PMC9513079 DOI: 10.1038/s41420-022-01193-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/12/2022] [Accepted: 09/16/2022] [Indexed: 11/09/2022] Open
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by cytogenetic and genomic alterations. Up to now, combination chemotherapy remains the standard treatment for leukemia. However, many individuals diagnosed with AML develop chemotherapeutic resistance and relapse. Recently, it has been pointed out that leukemic stem cells (LSCs) are the fundamental cause of drug resistance and AML relapse. LSCs only account for a small subpopulation of all leukemic cells, but possess stem cell properties, including a self-renewal capacity and a multi-directional differentiation potential. LSCs reside in a mostly quiescent state and are insensitive to chemotherapeutic agents. When LSCs reside in a bone marrow microenvironment (BMM) favorable to their survival, they engage into a steady, continuous clonal evolution to better adapt to the action of chemotherapy. Most chemotherapeutic drugs can only eliminate LSC-derived clones, reducing the number of leukemic cells in the BM to a normal range in order to achieve complete remission (CR). LSCs hidden in the BM niche can hardly be targeted or eradicated, leading to drug resistance and AML relapse. Understanding the relationship between LSCs, the BMM, and the generation and evolution laws of LSCs can facilitate the development of effective therapeutic targets and increase the efficiency of LSCs elimination in AML.
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Affiliation(s)
- Yongfeng Chen
- Department of Basic Medical Sciences, Medical College of Taizhou University, Taizhou, Zhejiang, 318000, China.
| | - Jing Li
- Department of Histology and Embryology, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Linglong Xu
- Department of Hematology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, 318000, China
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania.
- Department of Hematology, Centre of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
| | - Zhenyou Zou
- Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, Guangxi, 545005, China.
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40
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Loiko AG, Sergeev AV, Genatullina AI, Monakhova MV, Kubareva EA, Dolinnaya NG, Gromova ES. Impact of G-Quadruplex Structures on Methylation of Model Substrates by DNA Methyltransferase Dnmt3a. Int J Mol Sci 2022; 23:ijms231810226. [PMID: 36142137 PMCID: PMC9499004 DOI: 10.3390/ijms231810226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/28/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
In mammals, de novo methylation of cytosines in DNA CpG sites is performed by DNA methyltransferase Dnmt3a. Changes in the methylation status of CpG islands are critical for gene regulation and for the progression of some cancers. Recently, the potential involvement of DNA G-quadruplexes (G4s) in methylation control has been found. Here, we provide evidence for a link between G4 formation and the function of murine DNA methyltransferase Dnmt3a and its individual domains. As DNA models, we used (i) an isolated G4 formed by oligonucleotide capable of folding into parallel quadruplex and (ii) the same G4 inserted into a double-stranded DNA bearing several CpG sites. Using electrophoretic mobility shift and fluorescence polarization assays, we showed that the Dnmt3a catalytic domain (Dnmt3a-CD), in contrast to regulatory PWWP domain, effectively binds the G4 structure formed in both DNA models. The G4-forming oligonucleotide displaced the DNA substrate from its complex with Dnmt3a-CD, resulting in a dramatic suppression of the enzyme activity. In addition, a direct impact of G4 inserted into the DNA duplex on the methylation of a specific CpG site was revealed. Possible mechanisms of G4-mediated epigenetic regulation may include Dnmt3a sequestration at G4 and/or disruption of Dnmt3a oligomerization on the DNA surface.
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Affiliation(s)
- Andrei G. Loiko
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
- Correspondence: (A.G.L.); (A.V.S.)
| | - Alexander V. Sergeev
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
- Correspondence: (A.G.L.); (A.V.S.)
| | - Adelya I. Genatullina
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
| | - Mayya V. Monakhova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
| | - Elena A. Kubareva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
| | - Nina G. Dolinnaya
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
| | - Elizaveta S. Gromova
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia
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DNA methyltransferase DNMT3A forms interaction networks with the CpG site and flanking sequence elements for efficient methylation. J Biol Chem 2022; 298:102462. [PMID: 36067881 PMCID: PMC9530848 DOI: 10.1016/j.jbc.2022.102462] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/21/2022] Open
Abstract
Specific DNA methylation at CpG and non-CpG sites is essential for chromatin regulation. The DNA methyltransferase DNMT3A interacts with target sites surrounded by variable DNA sequences with its TRD and RD loops, but the functional necessity of these interactions is unclear. We investigated CpG and non-CpG methylation in a randomized sequence context using WT DNMT3A and several DNMT3A variants containing mutations at DNA-interacting residues. Our data revealed that the flanking sequence of target sites between the −2 and up to the +8 position modulates methylation rates >100-fold. Non-CpG methylation flanking preferences were even stronger and favor C(+1). R836 and N838 in concert mediate recognition of the CpG guanine. R836 changes its conformation in a flanking sequence-dependent manner and either contacts the CpG guanine or the +1/+2 flank, thereby coupling the interaction with both sequence elements. R836 suppresses activity at CNT sites but supports methylation of CAC substrates, the preferred target for non-CpG methylation of DNMT3A in cells. N838 helps to balance this effect and prevent the preference for C(+1) from becoming too strong. Surprisingly, we found L883 reduces DNMT3A activity despite being highly conserved in evolution. However, mutations at L883 disrupt the DNMT3A-specific DNA interactions of the RD loop, leading to altered flanking sequence preferences. Similar effects occur after the R882H mutation in cancer cells. Our data reveal that DNMT3A forms flexible and interdependent interaction networks with the CpG guanine and flanking residues that ensure recognition of the CpG and efficient methylation of the cytosine in contexts of variable flanking sequences.
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Ahmed YW, Alemu BA, Bekele SA, Gizaw ST, Zerihun MF, Wabalo EK, Teklemariam MD, Mihrete TK, Hanurry EY, Amogne TG, Gebrehiwot AD, Berga TN, Haile EA, Edo DO, Alemu BD. Epigenetic tumor heterogeneity in the era of single-cell profiling with nanopore sequencing. Clin Epigenetics 2022; 14:107. [PMID: 36030244 PMCID: PMC9419648 DOI: 10.1186/s13148-022-01323-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 08/12/2022] [Indexed: 11/29/2022] Open
Abstract
Nanopore sequencing has brought the technology to the next generation in the science of sequencing. This is achieved through research advancing on: pore efficiency, creating mechanisms to control DNA translocation, enhancing signal-to-noise ratio, and expanding to long-read ranges. Heterogeneity regarding epigenetics would be broad as mutations in the epigenome are sensitive to cause new challenges in cancer research. Epigenetic enzymes which catalyze DNA methylation and histone modification are dysregulated in cancer cells and cause numerous heterogeneous clones to evolve. Detection of this heterogeneity in these clones plays an indispensable role in the treatment of various cancer types. With single-cell profiling, the nanopore sequencing technology could provide a simple sequence at long reads and is expected to be used soon at the bedside or doctor's office. Here, we review the advancements of nanopore sequencing and its use in the detection of epigenetic heterogeneity in cancer.
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Affiliation(s)
- Yohannis Wondwosen Ahmed
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia.
| | - Berhan Ababaw Alemu
- Department of Medical Biochemistry, School of Medicine, St. Paul's Hospital, Millennium Medical College, Addis Ababa, Ethiopia
| | - Sisay Addisu Bekele
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Solomon Tebeje Gizaw
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Muluken Fekadie Zerihun
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Endriyas Kelta Wabalo
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Maria Degef Teklemariam
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Tsehayneh Kelemu Mihrete
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Endris Yibru Hanurry
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Tensae Gebru Amogne
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Assaye Desalegne Gebrehiwot
- Department of Medical Anatomy, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Tamirat Nida Berga
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Ebsitu Abate Haile
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Dessiet Oma Edo
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P.O. Box: 9086, Addis Ababa, Ethiopia
| | - Bizuwork Derebew Alemu
- Department of Statistics, College of Natural and Computational Sciences, Mizan Tepi University, Tepi, Ethiopia
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Muylaert C, Van Hemelrijck LA, Maes A, De Veirman K, Menu E, Vanderkerken K, De Bruyne E. Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity? Front Oncol 2022; 12:979569. [PMID: 36059621 PMCID: PMC9434119 DOI: 10.3389/fonc.2022.979569] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/22/2022] [Indexed: 11/30/2022] Open
Abstract
Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.
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Ashok A, Pooranawattanakul S, Tai WL, Cho KS, Utheim TP, Cestari DM, Chen DF. Epigenetic Regulation of Optic Nerve Development, Protection, and Repair. Int J Mol Sci 2022; 23:8927. [PMID: 36012190 PMCID: PMC9408916 DOI: 10.3390/ijms23168927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/07/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Epigenetic factors are known to influence tissue development, functionality, and their response to pathophysiology. This review will focus on different types of epigenetic regulators and their associated molecular apparatus that affect the optic nerve. A comprehensive understanding of epigenetic regulation in optic nerve development and homeostasis will help us unravel novel molecular pathways and pave the way to design blueprints for effective therapeutics to address optic nerve protection, repair, and regeneration.
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Affiliation(s)
- Ajay Ashok
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Sarita Pooranawattanakul
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Wai Lydia Tai
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Kin-Sang Cho
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Tor P. Utheim
- Department of Medical Biochemistry, Oslo University Hospital, 0372 Oslo, Norway
- Department of Ophthalmology, Oslo University Hospital, 0372 Oslo, Norway
| | - Dean M. Cestari
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Dong Feng Chen
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
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45
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Cao YL, -Zhu L, Zhang H, Meng JH, Wu HJ, Wang X, Wu JH, Zou JL, Fang MS, An J, Chen YG. Total Barley Maiya Alkaloids Prevent Increased Prolactin Levels Caused by Antipsychotic Drugs and Reduce Dopamine Receptor D2 via Epigenetic Mechanisms. Front Pharmacol 2022; 13:888522. [PMID: 35865960 PMCID: PMC9294270 DOI: 10.3389/fphar.2022.888522] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The dopamine D2 receptor (DRD2) plays an important role in the increased prolactin (PRL) levels associated with the pathogenesis of antipsychotic drugs (ADs). Elevated prolactin levels can affect people’s quality of life. Maiya alkaloids has been used to treat diseases associated with high PRL levels. Maiya, is a processed product of the mature fruits of Hordeum vulgare L. (a gramineous plant) after sprouting and drying and also a common Chinese herbal drug used in the clinic, is traditionally used to treat abnormal lactation, and is currently used clinically for the treatment of abnormal PRL levels.Aims: Epigenetic mechanisms can be related to DRD2 expression. We investigated the role of DRD2 methylation in the induction of PRL expression by ADs and the mechanism underlying the effects of total barley maiya alkaloids (TBMA) on this induction.Methods: The methylation rate of DRD2 in 46 people with schizophrenia who took risperidone was detected by MassARRAY sequencing. Humans were long term users of Ris. Seventy Sprague Dawley female rats were divided into seven groups. A rat model of risperidone-induced PRL was established, and the potential protective effects of TBMA and its components [e.g., hordenine (Hor)] on these increased PRL levels were investigated. The PRL concentration was detected by Enzyme-linked immunosorbent assay. PRL, DRD2, and DNA methyltransferase (DNMT1, DNMT3α, and DNMT3β) protein and mRNA expression were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The positive rate of methylation in the DRD2 promoter region of rats was detected by MassARRAY sequencing.Results: Clinical studies showed that the positive rate of DRD2 methylation associated with increased PRL levels induced by ADs was significantly higher than in the normal prolactinemia (NPRL) group. In vivo and vitro, TBMA and Hor inhibited this induction of PRL expression and increased DRD2 expression by inhibiting the expression of the DNMTs.Conclusions: TBMA and hordenine increased DRD2 expression by inhibiting DNMT-dependent DRD2 methylation.
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Affiliation(s)
- Yu-Ling Cao
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
- Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Li -Zhu
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
| | - Hong Zhang
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
- Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Jun-Hua Meng
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
| | - Hua-Jun Wu
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
| | - Xiong Wang
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
| | - Jin-Hu Wu
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
| | - Ji-Li Zou
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
| | - Mao-Sheng Fang
- Department of Psychiatry, Wuhan Mental Health Center, Wuhan, China
| | - Jing An
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
- *Correspondence: Jing An, ; Yong-Gang Chen,
| | - Yong-Gang Chen
- Pharmacy Department of Wuhan University Tongren Hospital (The Third Hospital of Wuhan), Wuhan, China
- *Correspondence: Jing An, ; Yong-Gang Chen,
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Ai K, Li X, Zhang P, Pan J, Li H, He Z, Zhang H, Yi L, Kang Y, Wang Y, Chen J, Li Y, Xiang X, Chai X, Zhang D. Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 28:77-86. [PMID: 35356685 PMCID: PMC8933641 DOI: 10.1016/j.omtn.2022.02.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 02/25/2022] [Indexed: 12/20/2022]
Abstract
DNA methylation plays a pivotal role in the progression of renal fibrosis. Methyl-CpG–binding domain protein 2 (MBD2), a protein reader of methylation, is involved in the development of acute kidney injury (AKI) caused by vancomycin. However, the role and mechanism of action of MBD2 in renal remain unclear. In this study, MBD2 mediated extracellular matrix (ECM) production induced by TGF-β1 in Boston University mouse proximal tubule (BUMPT) cells，and upregulated the expression EGR1 to promote ECM production in murine embryonic NIH 3T3 fibroblasts. ChIP analysis demonstrated that MBD2 physically interacted with the promoter region of the CpG islands of EGR1 genes and then activated their expression by inducing hypomethylation of the promoter region. In vivo, PT-MBD2-KO attenuated unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis via downregulation of EGR1, which was demonstrated by the downregulation of fibronectin (FN), collagen I and IV, α-SMA, and EGR1. Injection of MBD2-siRNA attenuated the UUO- and I/R-induced renal fibrosis. Those molecular changes were verified by biopsies from patients with obstructive nephropathy (OB). These data collectively demonstrated that inhibition of MBD2 reduces renal fibrosis via downregulating EGR1, which could be a target for treatment of fibrotic kidney disease.
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Affiliation(s)
- Kai Ai
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Xiaozhou Li
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Pan Zhang
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Jian Pan
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Huiling Li
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Zhibiao He
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Hongliang Zhang
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Lei Yi
- Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Ye Kang
- Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Yinhuai Wang
- Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Junxiang Chen
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Yijian Li
- Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Xudong Xiang
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Xiangping Chai
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Dongshan Zhang
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
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Ding J, Jiang H, Su B, Wang S, Chen X, Tan Y, Shen L, Wang J, Shi M, Lin H, Zhang Z. DNMT1/miR-130a/ZEB1 Regulatory Pathway Affects the Inflammatory Response in Lipopolysaccharide-Induced Sepsis. DNA Cell Biol 2022; 41:479-486. [PMID: 35486848 DOI: 10.1089/dna.2021.1060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Sepsis is a global health care issue that affects millions of people. DNA methyltransferase I (DNMT1)-mediated DNA methylation is involved in a number of human diseases by affecting many types of cellular progression events. However, the role and underlying molecular mechanism of DNMT1 in development of sepsis remain largely unknown. Lipopolysaccharide (LPS) induced lung fibrosis in the sepsis mouse model, and DNMT1 was upregulated in lung tissues of a sepsis mouse model compared with lung tissues from control mice. Then, this study demonstrated that LPS induced the production of interleukin (IL)-7 and tumor necrosis factor (TNF)-α and promoted DNMT1 expression in primary type II alveolar epithelial cells (AECII cells). Knockdown of DNMT1 inhibited IL-7 and TNF-α secretion in AECII cells exposed to LPS. Further study demonstrated that DNMT1 repressed the expression of miR-130a in AECII cells with or without LPS exposure. Next, this study demonstrated that miR-130a inhibited ZEB1 expression in AECII cells exposed to LPS. Ultimately, this study revealed the role of the DNMT1/miR-130a/ZEB1 regulatory pathway in AECII cells exposed to LPS. Overall, our data revealed that LPS induced the secretion of inflammatory factors by modulating the DNMT1/miR-130a/ZEB1 regulatory pathway in AECII cells, thus providing a novel theoretical basis that might be beneficial for establishment of diagnostic and therapeutic strategies for sepsis.
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Affiliation(s)
- Jurong Ding
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongbin Jiang
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bo Su
- Department of Central Laboratory, and Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shanmei Wang
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaolan Chen
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanlin Tan
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Li Shen
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingjing Wang
- Department of Emergency, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Minxing Shi
- Department of Respirology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haixu Lin
- Department of Central Laboratory, and Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhemin Zhang
- Department of Respirology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
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Zhu L, Jia L, Liu N, Wu R, Guan G, Hui R, Xing Y, Zhang Y, Wang J. DNA Methyltransferase 3b Accelerates the Process of Atherosclerosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5249367. [PMID: 35422896 PMCID: PMC9005271 DOI: 10.1155/2022/5249367] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/09/2022] [Indexed: 12/23/2022]
Abstract
Background DNA methylation plays a key role in establishing cell type-specific gene expression profiles and patterns in atherosclerosis. The underlying mechanism remains unclear. Previous studies have shown that DNA methyltransferase 3b (DNMT3b) may play an important role in atherosclerosis. This study aimed to establish the regulatory role of DNMT3b in the development of atherosclerosis. Methods We constructed a viral vector carrying Dnmt3b shRNA to transduce ApoE-/- mice. Meanwhile, healthy human peripheral blood Treg cells were treated with inhibitor of DNMT3b (AZA and EGCG) or transduced with DNMT3b shRNA. Results It showed that Dnmt3b silencing attenuated atherosclerosis, including decreased lesion size and macrophage content and increased collagen and smooth muscle cells content in ApoE-/- mice. To further investigate the possible mechanisms, combined with previous studies by our group, we showed that Foxp3-TSDR methylation level was significantly reduced Foxp3 expression and peripheral blood Treg levels were significantly increased by Dnmt3b shRNA vector transduction in animals committed to western diet for 12 and 18 weeks. Consistently, inhibition of DNMT3b (AZA and EGCG) decreased the expression levels of DNMT3b, which can increase the expression levels of FOXP3, and increase the levels of TGF-β and IL-10 and decrease the levels of IL-β and IFN-γ. After transduction with DNMT3b shRNA, the effect was more obvious. Conclusions DNMT3b accelerated atherosclerosis, and may be associated with FOXP3 hypermethylation status in regulatory T cells.
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Affiliation(s)
- Ling Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
- Department of Cardiology, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, China
| | - Lei Jia
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Na Liu
- Department of Pediatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
| | - Runmiao Wu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
| | - Gongchang Guan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
| | - Rutai Hui
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Yujie Xing
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
| | - Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
| | - Junkui Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710000, China
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Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics. Cancers (Basel) 2022; 14:cancers14061469. [PMID: 35326620 PMCID: PMC8946119 DOI: 10.3390/cancers14061469] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/23/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023] Open
Abstract
Lymphoma is a neoplasm arising from B or T lymphocytes or natural killer cells characterized by clonal lymphoproliferation. This tumor comprises a diverse and heterogeneous group of malignancies with distinct clinical, histopathological, and molecular characteristics. Despite advances in lymphoma treatment, clinical outcomes of patients with relapsed or refractory disease remain poor. Thus, a deeper understanding of molecular pathogenesis and tumor progression of lymphoma is required. Epigenetic alterations contribute to cancer initiation, progression, and drug resistance. In fact, over the past decade, dysregulation of epigenetic mechanisms has been identified in lymphomas, and the knowledge of the epigenetic aberrations has led to the emergence of the promising epigenetic therapy field in lymphoma tumors. However, epigenetic aberrations in lymphoma not only have been found in tumor cells, but also in cells from the tumor microenvironment, such as immune cells. Whereas the epigenetic dysregulation in lymphoma cells is being intensively investigated, there are limited studies regarding the epigenetic mechanisms that affect the functions of immune cells from the tumor microenvironment in lymphoma. Therefore, this review tries to provide a general overview of epigenetic alterations that affect both lymphoma cells and infiltrating immune cells within the tumor, as well as the epigenetic cross-talk between them.
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Kitazawa S, Ohno T, Haraguchi R, Kitazawa R. Histochemistry, Cytochemistry and Epigenetics. Acta Histochem Cytochem 2022; 55:1-7. [PMID: 35444348 PMCID: PMC8913277 DOI: 10.1267/ahc.21-00095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 12/27/2021] [Indexed: 12/23/2022] Open
Abstract
Over the past few decades, many researchers have individually identified tumor-related genes, and have accumulated information on their basic research in a database. With the development of technology that can comprehensively test the expression status within a short time, oncogene panel testing has become attainable. On the other hand, changes in gene expression that do not depend on changes in base sequences, that is, epigenetics, or more comprehensively, epigenomes, are also highly involved in the development and progression of disease. Oncogene panel tests tend to focus on DNA base mutations such as point mutations, deletions, duplications, and chimera formation. Elucidation leads to correct interpretation of diseases and treatment choices, and we are in an era where integrated understanding of the genome and epigenome is indispensable. In this review, we make every effort to cover a wide range of knowledge, including data on histone protein modification, non-coding (nc)RNA and DNA methylation, and recent application trials for demonstrating epigenetic alterations in histologic and cytologic specimens. We hope this review will help marshal the knowledge accumulated by researchers involved in genomic and epigenomic studies.
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Affiliation(s)
- Sohei Kitazawa
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
| | - Teruyuki Ohno
- Division of Diagnostic Pathology, Ehime University Hospital
| | - Ryuma Haraguchi
- Department of Molecular Pathology, Ehime University Graduate School of Medicine
| | - Riko Kitazawa
- Division of Diagnostic Pathology, Ehime University Hospital
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