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1
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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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Tibben BM, Rothbart SB. Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation. J Mol Biol 2024; 436:168394. [PMID: 38092287 PMCID: PMC10957332 DOI: 10.1016/j.jmb.2023.168394] [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: 09/28/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023]
Abstract
DNA methylation is a well-studied epigenetic modification that has key roles in regulating gene expression, maintaining genome integrity, and determining cell fate. Precisely how DNA methylation patterns are established and maintained in specific cell types at key developmental stages is still being elucidated. However, research over the last two decades has contributed to our understanding of DNA methylation regulation by other epigenetic processes. Specifically, lysine methylation on key residues of histone proteins has been shown to contribute to the allosteric regulation of DNA methyltransferase (DNMT) activities. In this review, we discuss the dynamic interplay between DNA methylation and histone lysine methylation as epigenetic regulators of genome function by synthesizing key recent studies in the field. With a focus on DNMT3 enzymes, we discuss mechanisms of DNA methylation and histone lysine methylation crosstalk in the regulation of gene expression and the maintenance of genome integrity. Further, we discuss how alterations to the balance of various sites of histone lysine methylation and DNA methylation contribute to human developmental disorders and cancers. Finally, we provide perspectives on the current direction of the field and highlight areas for continued research and development.
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Affiliation(s)
- Bailey M Tibben
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Scott B Rothbart
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
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3
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Taglini F, Kafetzopoulos I, Rolls W, Musialik KI, Lee HY, Zhang Y, Marenda M, Kerr L, Finan H, Rubio-Ramon C, Gautier P, Wapenaar H, Kumar D, Davidson-Smith H, Wills J, Murphy LC, Wheeler A, Wilson MD, Sproul D. DNMT3B PWWP mutations cause hypermethylation of heterochromatin. EMBO Rep 2024; 25:1130-1155. [PMID: 38291337 PMCID: PMC7615734 DOI: 10.1038/s44319-024-00061-5] [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: 04/18/2023] [Revised: 12/21/2023] [Accepted: 12/21/2023] [Indexed: 02/01/2024] Open
Abstract
The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions at heterochromatin through an unknown recruitment mechanism. Here, we find that knockout of DNMT3B causes loss of methylation predominantly at H3K9me3-marked heterochromatin and that DNMT3B PWWP domain mutations or deletion result in striking increases of methylation in H3K9me3-marked heterochromatin. Removal of the N-terminal region of DNMT3B affects its ability to methylate H3K9me3-marked regions. This region of DNMT3B directly interacts with HP1α and facilitates the bridging of DNMT3B with H3K9me3-marked nucleosomes in vitro. Our results suggest that DNMT3B is recruited to H3K9me3-marked heterochromatin in a PWWP-independent manner that is facilitated by the protein's N-terminal region through an interaction with a key heterochromatin protein. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in cancer, aging and Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome.
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Affiliation(s)
- Francesca Taglini
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ioannis Kafetzopoulos
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Altos Labs, Cambridge Institute, Cambridge, UK
| | - Willow Rolls
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
| | - Kamila Irena Musialik
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- MRC London Institute of Medical Sciences and Institute of Clinical Sciences, Imperial College London, London, UK
| | - Heng Yang Lee
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Endocrine Oncology Research Group, Department of Surgery, The Royal College of Surgeons RCSI, University of Medicine and Health Sciences, Dublin, Ireland
| | - Yujie Zhang
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
| | - Mattia Marenda
- IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy
| | - Lyndsay Kerr
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK
| | - Hannah Finan
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Swiss Federal Institute of Technology, ETH Zürich, Institute of Molecular Health Sciences, Zürich, Switzerland
| | - Cristina Rubio-Ramon
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France
| | - Philippe Gautier
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Hannah Wapenaar
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
| | - Dhananjay Kumar
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
| | - Hazel Davidson-Smith
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Jimi Wills
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Laura C Murphy
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ann Wheeler
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Marcus D Wilson
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
| | - Duncan Sproul
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
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Loaeza-Loaeza J, Cerecedo-Castillo AJ, Rodríguez-Ruiz HA, Castro-Coronel Y, Del Moral-Hernández O, Recillas-Targa F, Hernández-Sotelo D. DNMT3B overexpression downregulates genes with CpG islands, common motifs, and transcription factor binding sites that interact with DNMT3B. Sci Rep 2022; 12:20839. [PMID: 36460706 PMCID: PMC9718745 DOI: 10.1038/s41598-022-24186-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 11/11/2022] [Indexed: 12/04/2022] Open
Abstract
DNA methylation is a key epigenetic modification to regulate gene expression in mammalian cells. Abnormal DNA methylation in gene promoters is common across human cancer types. DNMT3B is the main de novo methyltransferase enhanced in several primary tumors. How de novo methylation is established in genes related to cancer is poorly understood. CpG islands (CGIs), common sequences, and transcription factors (TFs) that interact with DNMT3B have been associated with abnormal de novo methylation. We initially identified cis elements associated with DNA methylation to investigate the contribution of DNMT3B overexpression to the deregulation of its possible target genes in an epithelial cell model. In a set of downregulated genes (n = 146) from HaCaT cells with DNMT3B overexpression, we found CGI, common sequences, and TFs Binding Sites that interact with DNMT3B (we called them P-down-3B). PPL1, VAV3, IRF1, and BRAF are P-down-3B genes that are downregulated and increased their methylation in DNMT3B presence. Together these findings suggest that methylated promoters aberrantly have some cis elements that could conduce de novo methylation by DNMT3B.
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Affiliation(s)
- Jaqueline Loaeza-Loaeza
- grid.412856.c0000 0001 0699 2934Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Angel Josué Cerecedo-Castillo
- grid.9486.30000 0001 2159 0001Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico
| | - Hugo Alberto Rodríguez-Ruiz
- grid.412856.c0000 0001 0699 2934Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Yaneth Castro-Coronel
- grid.412856.c0000 0001 0699 2934Laboratorio de Citopatología e Inmunohistoquímica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Oscar Del Moral-Hernández
- grid.412856.c0000 0001 0699 2934Laboratorio de Virus y Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
| | - Félix Recillas-Targa
- grid.9486.30000 0001 2159 0001Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico
| | - Daniel Hernández-Sotelo
- grid.412856.c0000 0001 0699 2934Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N Col. Haciendita, 39070 Chilpancingo, Guerrero Mexico
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Chen X, Zhou W, Song RH, Liu S, Wang S, Chen Y, Gao C, He C, Xiao J, Zhang L, Wang T, Liu P, Duan K, Cheng Z, Zhang C, Zhang J, Sun Y, Jackson F, Lan F, Liu Y, Xu Y, Wong JJL, Wang P, Yang H, Xiong Y, Chen T, Li Y, Ye D. Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity. SCIENCE ADVANCES 2022; 8:eabl5220. [PMID: 35080973 PMCID: PMC8791617 DOI: 10.1126/sciadv.abl5220] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPAN321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPAN321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA-mutated leukemia with DNA-hypomethylating agents.
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Affiliation(s)
- Xiufei Chen
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Target Discovery Institute, NDM Research Building, Oxford Ludwig Institute of Cancer Research, Oxford University, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK
| | - Wenjie Zhou
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ren-Hua Song
- Epigenetics and RNA Biology Program, Centenary Institute, The University of Sydney, Camperdown 2050, Australia
| | - Shuang Liu
- MOE Key Laboratory of Model Animals for Disease Study, Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing, China
| | - Shu Wang
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yujia Chen
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chao Gao
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chenxi He
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jianxiong Xiao
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lei Zhang
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Tianxiang Wang
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Peng Liu
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Kunlong Duan
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhouli Cheng
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chen Zhang
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jinye Zhang
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yiping Sun
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Felix Jackson
- Department of Computer Science, University of Oxford, 15 Parks Rd, Oxford OX1 3QD, UK
| | - Fei Lan
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yun Liu
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yanhui Xu
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Justin Jong-Leong Wong
- Epigenetics and RNA Biology Program, Centenary Institute, The University of Sydney, Camperdown 2050, Australia
| | - Pu Wang
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yue Xiong
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Tong Chen
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
- Corresponding author. (T.C.); (Yan Li); (D.Y.)
| | - Yan Li
- MOE Key Laboratory of Model Animals for Disease Study, Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing, China
- Corresponding author. (T.C.); (Yan Li); (D.Y.)
| | - Dan Ye
- Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Corresponding author. (T.C.); (Yan Li); (D.Y.)
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Jurkowska RZ, Jeltsch A. Enzymology of Mammalian DNA Methyltransferases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1389:69-110. [DOI: 10.1007/978-3-031-11454-0_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Ko EK, Capell BC. Methyltransferases in the Pathogenesis of Keratinocyte Cancers. Cancers (Basel) 2021; 13:cancers13143402. [PMID: 34298617 PMCID: PMC8304454 DOI: 10.3390/cancers13143402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/02/2021] [Accepted: 07/04/2021] [Indexed: 12/13/2022] Open
Abstract
Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively outnumber all other human cancers combined. While it is clear that methylation modifiers are frequently dysregulated in KCs, the underlying molecular and mechanistic changes are only beginning to be understood. Intriguingly, it has recently emerged that there is extensive cross-talk amongst these distinct methylation processes. Here, we summarize and synthesize the latest findings in this space and highlight how these discoveries may uncover novel therapeutic approaches for these ubiquitous cancers.
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Affiliation(s)
- Eun Kyung Ko
- Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Brian C. Capell
- Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA;
- Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Penn Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Correspondence:
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Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis. Microorganisms 2021; 9:microorganisms9061179. [PMID: 34070716 PMCID: PMC8227491 DOI: 10.3390/microorganisms9061179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.
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Han M, Li J, Cao Y, Huang Y, Li W, Zhu H, Zhao Q, Han JDJ, Wu Q, Li J, Feng J, Wong J. A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association. Nucleic Acids Res 2020; 48:12116-12134. [PMID: 33170271 PMCID: PMC7708066 DOI: 10.1093/nar/gkaa1003] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/23/2020] [Accepted: 10/14/2020] [Indexed: 12/25/2022] Open
Abstract
LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin.
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Affiliation(s)
- Mengmeng Han
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jialun Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai 201499, China
| | - Yaqiang Cao
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Room122, 320 Yue Yang Road, Shanghai 200031, China
| | - Yuanyong Huang
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Wen Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Haijun Zhu
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 200032, China
| | - Qian Zhao
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jing-Dong Jackie Han
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Room122, 320 Yue Yang Road, Shanghai 200031, China
| | - Qihan Wu
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 200032, China
| | - Jiwen Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jing Feng
- Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai 201499, China
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499, China
| | - Jiemin Wong
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai 201499, China
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10
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Mederer T, Schmitteckert S, Volz J, Martínez C, Röth R, Thumberger T, Eckstein V, Scheuerer J, Thöni C, Lasitschka F, Carstensen L, Günther P, Holland-Cunz S, Hofstra R, Brosens E, Rosenfeld JA, Schaaf CP, Schriemer D, Ceccherini I, Rusmini M, Tilghman J, Luzón-Toro B, Torroglosa A, Borrego S, Sze-man Tang C, Garcia-Barceló M, Tam P, Paramasivam N, Bewerunge-Hudler M, De La Torre C, Gretz N, Rappold GA, Romero P, Niesler B. A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet 2020; 16:e1009106. [PMID: 33151932 PMCID: PMC7643938 DOI: 10.1371/journal.pgen.1009106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 09/08/2020] [Indexed: 11/24/2022] Open
Abstract
Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.
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Affiliation(s)
- Tanja Mederer
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefanie Schmitteckert
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Julia Volz
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Cristina Martínez
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
- Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Lleida, Spain
| | - Ralph Röth
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
- nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Thumberger
- Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany
| | | | - Jutta Scheuerer
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Cornelia Thöni
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Felix Lasitschka
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Leonie Carstensen
- Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany
| | - Patrick Günther
- Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Robert Hofstra
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Erwin Brosens
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jill A. Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
- Baylor Genetics Laboratories, Houston, Texas, United States of America
| | - Christian P. Schaaf
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
- Baylor Genetics Laboratories, Houston, Texas, United States of America
- Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Duco Schriemer
- Department of Neuroscience, University Medical Center, Groningen, The Netherlands
| | - Isabella Ceccherini
- UOSD Genetica e Genomica delle Malattie Rare, IRCCS, Instituto Giannina Gaslini, Genova, Italy
| | - Marta Rusmini
- UOSD Genetica e Genomica delle Malattie Rare, IRCCS, Instituto Giannina Gaslini, Genova, Italy
| | - Joseph Tilghman
- Center for Human Genetics and Genomics, New York University School of Medicine, United States of America
| | - Berta Luzón-Toro
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Ana Torroglosa
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Salud Borrego
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Clara Sze-man Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Mercè Garcia-Barceló
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Paul Tam
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Nagarajan Paramasivam
- Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany
| | | | | | - Norbert Gretz
- Center of Medical Research, Medical Faculty Mannheim, Mannheim, Germany
| | - Gudrun A. Rappold
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
- Interdisciplinary Center for Neurosciences, University of Heidelberg, Heidelberg, Germany
| | - Philipp Romero
- Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
- nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
- Interdisciplinary Center for Neurosciences, University of Heidelberg, Heidelberg, Germany
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11
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Wang J, Yang J, Li D, Li J. Technologies for targeting DNA methylation modifications: Basic mechanism and potential application in cancer. Biochim Biophys Acta Rev Cancer 2020; 1875:188454. [PMID: 33075468 DOI: 10.1016/j.bbcan.2020.188454] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/14/2020] [Accepted: 10/14/2020] [Indexed: 02/07/2023]
Abstract
DNA methylation abnormalities are regarded as critical event for cancer initiation and development. Tumor-associated genes encompassing aberrant DNA methylation alterations at specific locus are correlated with chromatin remodeling and dysregulation of gene expression in various malignancies. Thus, technologies designed to manipulate DNA methylation at specific loci of genome are necessary for the functional study and therapeutic application in the context of cancer management. Traditionally, the method for DNA methylation modifications demonstrates an unspecific feature, adversely causing global-genome epigenetic alterations and confusing the function of desired gene. Novel approaches for targeted DNA methylation regulation have a great advantage of manipulating gene epigenetic alterations in a more specific and efficient method. In this review, we described different targeting DNA methylation techniques, including both their advantages and limitations. Through a comprehensive understanding of these targeting tools, we hope to open a new perspective for cancer treatment.
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Affiliation(s)
- Jie Wang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, P.R. China
| | - Jing Yang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, P.R. China
| | - Dandan Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, P.R. China
| | - Jinming Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, P.R. China.
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12
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Xu TH, Liu M, Zhou XE, Liang G, Zhao G, Xu HE, Melcher K, Jones PA. Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature 2020; 586:151-155. [PMID: 32968275 PMCID: PMC7540737 DOI: 10.1038/s41586-020-2747-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 06/30/2020] [Indexed: 12/31/2022]
Abstract
CpG methylation by de novo DNA methyltransferases (DNMTs) 3A and 3B is essential for mammalian development and differentiation and is frequently dysregulated in cancer1. These two DNMTs preferentially bind to nucleosomes, yet cannot methylate the DNA wrapped around the nucleosome core2, and they favour the methylation of linker DNA at positioned nucleosomes3,4. Here we present the cryo-electron microscopy structure of a ternary complex of catalytically competent DNMT3A2, the catalytically inactive accessory subunit DNMT3B3 and a nucleosome core particle flanked by linker DNA. The catalytic-like domain of the accessory DNMT3B3 binds to the acidic patch of the nucleosome core, which orients the binding of DNMT3A2 to the linker DNA. The steric constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur.
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Affiliation(s)
- Ting-Hai Xu
- Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI, USA
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Minmin Liu
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - X Edward Zhou
- Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI, USA
| | - Gangning Liang
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA, USA
| | - Gongpu Zhao
- David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Institute, Grand Rapids, MI, USA
| | - H Eric Xu
- Center for Structure and Function of Drug Targets, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
| | - Karsten Melcher
- Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI, USA.
| | - Peter A Jones
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
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13
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Saravanaraman P, Selvam M, Ashok C, Srijyothi L, Baluchamy S. De novo methyltransferases: Potential players in diseases and new directions for targeted therapy. Biochimie 2020; 176:85-102. [PMID: 32659446 DOI: 10.1016/j.biochi.2020.07.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 06/06/2020] [Accepted: 07/07/2020] [Indexed: 12/16/2022]
Abstract
Epigenetic modifications govern gene expression by guiding the human genome on 'what to express and what not to'. DNA methyltransferases (DNMTs) establish methylation patterns on DNA, particularly in CpG islands, and such patterns play a major role in gene silencing. DNMTs are a family of proteins/enzymes (DNMT1, 2, 3A, 3B, and 3L), among which, DNMT1 (maintenance methyltransferase) and DNMT3 (de novo methyltransferases) that direct mammalian development and genome imprinting are highly investigated. In recent decades, many studies revealed a strong association of DNA methylation patterns with gene expression in various clinical conditions. Differential expression of DNMT3 family proteins and their splice variants result in changes in methylation patterns and such alterations have been associated with the initiation and progression of various diseases, especially cancer. This review will discuss the aberrant modifications generated by DNMT3 proteins under various clinical conditions, suggesting a potential signature for de novo methyltransferases in targeted disease therapy. Further, this review discusses the possibility of using 'CpG island methylation signatures' as promising biomarkers and emphasizes 'targeted hypomethylation' by disrupting the interaction of specific DNMT-protein complexes as the future of cancer therapeutics.
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Affiliation(s)
- Ponne Saravanaraman
- Department of Biotechnology, Pondicherry Central University, Pondicherry, 605014, India
| | - Murugan Selvam
- Department of Biotechnology, Pondicherry Central University, Pondicherry, 605014, India
| | - Cheemala Ashok
- Department of Biotechnology, Pondicherry Central University, Pondicherry, 605014, India
| | - Loudu Srijyothi
- Department of Biotechnology, Pondicherry Central University, Pondicherry, 605014, India
| | - Sudhakar Baluchamy
- Department of Biotechnology, Pondicherry Central University, Pondicherry, 605014, India.
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14
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A Mathematical Model for Inheritance of DNA Methylation Patterns in Somatic Cells. Bull Math Biol 2020; 82:84. [PMID: 32613387 DOI: 10.1007/s11538-020-00765-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 06/10/2020] [Indexed: 12/22/2022]
Abstract
DNA methylation is an essential epigenetic mechanism used by cells to regulate gene expression. Interestingly, DNA replication, a function necessary for cell division, disrupts the methylation pattern. Since perturbed methylation patterns are associated with aberrant gene expression and many diseases, including cancer, restoration of the correct pattern following DNA replication is crucial. However, the exact mechanisms of this restoration remain under investigation. DNA methyltransferases (Dnmts) perform methylation by adding a methyl group to cytosines at CpG sites in the DNA. These CpG sites are found in regions of high density, termed CpG islands (CGIs), and regions of low density in the genome. Nearly, every CpG site in a CGI has the same state, either methylated or unmethylated, and almost all CpG sites in regions of low CpG density are methylated. We propose a stochastic model for the dynamics of the post-replicative restoration of methylation patterns. The model considers the recruitment of Dnmts and demethylating enzymes to regions of hyper- and hypomethylation, respectively. The model also includes the interaction between Dnmt1 and PCNA, an enzyme that localizes Dnmt1 to the replication complex. Using our model, we predict that the methylation of regions of DNA can be bistable. Further, we predict that recruitment mechanisms maintain methylation in CGIs, whereas the Dnmt1-PCNA interaction maintains methylation in low-density regions.
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15
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Dzobo K. Epigenomics-Guided Drug Development: Recent Advances in Solving the Cancer Treatment "jigsaw puzzle". OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2020; 23:70-85. [PMID: 30767728 DOI: 10.1089/omi.2018.0206] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade. Importantly, the coupling of epigenetic editing techniques, such as clustered regularly interspersed short palindromic repeat (CRISPR)-CRISPR-associated protein-9 (Cas9) and APOBEC-coupled epigenetic sequencing (ACE-seq) with epigenetic drug screens, will allow the identification of small-molecule inhibitors or drugs able to reverse epigenetic changes responsible for many diseases. In addition, concrete and sustainable innovation in cancer treatment ought to integrate epigenome targeting drugs with classic therapies such as chemotherapy and immunotherapy.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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16
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Zhang W, Klinkebiel D, Barger CJ, Pandey S, Guda C, Miller A, Akers SN, Odunsi K, Karpf AR. Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability. Cancers (Basel) 2020; 12:cancers12030764. [PMID: 32213861 PMCID: PMC7140107 DOI: 10.3390/cancers12030764] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 03/19/2020] [Indexed: 02/08/2023] Open
Abstract
A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 and CCNE1 overexpression. Furthermore, DNA hypomethylation in these tumors was enriched within genomic blocks (hypomethylated blocks) that overlapped late-replicating regions, lamina-associated domains, PRC2 binding sites, and the H3K27me3 histone mark. Increased proliferation coupled with hypomethylated blocks at late-replicating regions suggests a passive hypomethylation mechanism. This hypothesis was further supported by our observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO (+) EOC after normalization to canonical proliferation markers, including MKI67. Finally, GDHO (+) EOC tumors had elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at the DNA hypomethylated blocks. Together, these findings implicate a passive DNA demethylation mechanism in ovarian cancer that is associated with genomic instability and poor prognosis.
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Affiliation(s)
- Wa Zhang
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA; (W.Z.); (C.J.B.)
| | - David Klinkebiel
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; (D.K.); (C.G.)
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Carter J. Barger
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA; (W.Z.); (C.J.B.)
| | - Sanjit Pandey
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Chittibabu Guda
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; (D.K.); (C.G.)
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Austin Miller
- Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Stacey N. Akers
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.A.); (K.O.)
| | - Kunle Odunsi
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.A.); (K.O.)
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Adam R. Karpf
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA; (W.Z.); (C.J.B.)
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; (D.K.); (C.G.)
- Correspondence: ; Tel.: +1-402-559-6115; Fax: +1-402-599-4651
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17
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Ying Y, Li J, Xie H, Yan H, Jin K, He L, Ma X, Wu J, Xu X, Fang J, Wang X, Zheng X, Liu B, Xie L. CCND1, NOP14 and DNMT3B are involved in miR-502-5p-mediated inhibition of cell migration and proliferation in bladder cancer. Cell Prolif 2020; 53:e12751. [PMID: 31971654 PMCID: PMC7048215 DOI: 10.1111/cpr.12751] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/12/2019] [Accepted: 12/07/2019] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Downregulation of miR-502-5p has emerged as a critical factor in tumour progression in several cancers. Herein, we elucidated the role of miR-502-5p in bladder cancer. MATERIALS AND METHODS RT-qPCR was performed to examine the expression of miR-502-5p in bladder cancer. And DNA methylation analysis showed that epigenetic mechanisms may contribute to the downregulation of miR-502-5p. Then, wound-healing assay, transwell assay, colony formation assay, CCK8 assay and flow cytometry analysis were applied to evaluate the function of miR-502-5p in bladder cancer cell lines. Western blot was conducted to measure the protein levels of related genes. Furthermore, dual-luciferase reporter assay, in vivo tumorigenesis assay and immunohistochemical staining were also conducted as needed. RESULTS MiR-502-5p is frequently downregulated in BCa. Meanwhile, hypermethylation of CpG islands contributes to the downregulation of miR-502-5p. Functionally, overexpression of miR-502-5p inhibited cell proliferation and migration in vitro and repressed tumour growth in vivo. CCND1, DNMT3B and NOP14 were identified as direct targets of miR-502-5p. Interestingly, DNMT3B and miR-502-5p established a positive feedback loop in the regulation of bladder cancer. In addition, rescue experiments further validated the direct molecular interaction between miR-502-5p and its targets. CONCLUSIONS Our study proposed and demonstrated that the miR-502-5p-mediated regulatory network is critical in bladder cancer; this network may be useful in the development of more effective therapies against bladder cancer.
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Affiliation(s)
- Yufan Ying
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Jiangfeng Li
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Haiyun Xie
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Huaqing Yan
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Ke Jin
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Liujia He
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xueyou Ma
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Jian Wu
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xin Xu
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Jiajie Fang
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xiao Wang
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xiangyi Zheng
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Ben Liu
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Liping Xie
- Department of UrologySchool of MedicineFirst Affiliated Hospital of Zhejiang UniversityHangzhouChina
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18
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Goel D, Un Nisa K, Reza MI, Rahman Z, Aamer S. Aberrant DNA Methylation Pattern may Enhance Susceptibility to Migraine: A Novel Perspective. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2019; 18:504-515. [DOI: 10.2174/1871527318666190809162631] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 06/04/2019] [Accepted: 07/27/2019] [Indexed: 12/17/2022]
Abstract
In today’s world, migraine is one of the most frequent disorders with an estimated world prevalence of 14.7% characterized by attacks of a severe headache making people enfeebled and imposing a big socioeconomic burden. The pathophysiology of a migraine is not completely understood however there are pieces of evidence that epigenetics performs a primary role in the pathophysiology of migraine. Here, in this review, we highlight current evidence for an epigenetic link with migraine in particular DNA methylation of numerous genes involved in migraine pathogenesis. Outcomes of various studies have explained the function of DNA methylation of a several migraine related genes such as RAMP1, CALCA, NOS1, ESR1, MTHFR and NR4A3 in migraine pathogenesis. Mentioned data suggested there exist a strong association of DNA methylation of migraine-related genes in migraine. Although we now have a general understanding of the role of epigenetic modifications of a numerous migraine associated genes in migraine pathogenesis, there are many areas of active research are of key relevance to medicine. Future studies into the complexities of epigenetic modifications will bring a new understanding of the mechanisms of migraine processes and open novel approaches towards therapeutic intervention.
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Affiliation(s)
- Divya Goel
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research, Guwahati, India
| | - Kaiser Un Nisa
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research, SAS Nagar, India
| | - Mohammad Irshad Reza
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research, SAS Nagar, India
| | - Ziaur Rahman
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research, SAS Nagar, India
| | - Shaikh Aamer
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research, SAS Nagar, India
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19
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The Roles of Human DNA Methyltransferases and Their Isoforms in Shaping the Epigenome. Genes (Basel) 2019; 10:genes10020172. [PMID: 30813436 PMCID: PMC6409524 DOI: 10.3390/genes10020172] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/16/2019] [Accepted: 02/19/2019] [Indexed: 12/20/2022] Open
Abstract
A DNA sequence is the hard copy of the human genome and it is a driving force in determining the physiological processes in an organism. Concurrently, the chemical modification of the genome and its related histone proteins is dynamically involved in regulating physiological processes and diseases, which overall constitutes the epigenome network. Among the various forms of epigenetic modifications, DNA methylation at the C-5 position of cytosine in the cytosine–guanine (CpG) dinucleotide is one of the most well studied epigenetic modifications. DNA methyltransferases (DNMTs) are a family of enzymes involved in generating and maintaining CpG methylation across the genome. In mammalian systems, DNA methylation is performed by DNMT1 and DNMT3s (DNMT3A and 3B). DNMT1 is predominantly involved in the maintenance of DNA methylation during cell division, while DNMT3s are involved in establishing de novo cytosine methylation and maintenance in both embryonic and somatic cells. In general, all DNMTs require accessory proteins, such as ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domain 1 (UHRF1) or DNMT3-like (DNMT3L), for their biological function. This review mainly focuses on the role of DNMT3B and its isoforms in de novo methylation and maintenance of DNA methylation, especially with respect to their role as an accessory protein.
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20
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Easwaran H, Baylin SB. Origin and Mechanisms of DNA Methylation Dynamics in Cancers. RNA TECHNOLOGIES 2019. [DOI: 10.1007/978-3-030-14792-1_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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21
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Assis RIF, Wiench M, Silvério KG, da Silva RA, Feltran GDS, Sallum EA, Casati MZ, Nociti FH, Andia DC. RG108 increases NANOG and OCT4 in bone marrow-derived mesenchymal cells through global changes in DNA modifications and epigenetic activation. PLoS One 2018; 13:e0207873. [PMID: 30507955 PMCID: PMC6277091 DOI: 10.1371/journal.pone.0207873] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 11/06/2018] [Indexed: 01/08/2023] Open
Abstract
Human bone marrow-derived mesenchymal stem cells (hBMSCs) are important for tissue regeneration but their epigenetic regulation is not well understood. Here we investigate the ability of a non-nucleoside DNA methylation inhibitor, RG108 to induce epigenetic changes at both global and gene-specific levels in order to enhance mesenchymal cell markers, in hBMSCs. hBMSCs were treated with complete culture medium, 50 μM RG108 and DMSO for three days and subjected to viability and apoptosis assays, global and gene-specific methylation/hydroxymethylation, transcript levels’ analysis of epigenetic machinery enzymes and multipotency markers, protein activities of DNMTs and TETs, immunofluorescence staining and western blot analysis for NANOG and OCT4 and flow cytometry for CD105. The RG108, when used at 50 μM, did not affect the viability, apoptosis and proliferation rates of hBMSCs or hydroxymethylation global levels while leading to 75% decrease in DNMTs activity and 42% loss of global DNA methylation levels. In addition, DNMT1 was significantly downregulated while TET1 was upregulated, potentially contributing to the substantial loss of methylation observed. Most importantly, the mesenchymal cell markers CD105, NANOG and OCT4 were upregulated being NANOG and OCT4 epigenetically modulated by RG108, at their gene promoters. We propose that RG108 could be used for epigenetic modulation, promoting epigenetic activation of NANOG and OCT4, without affecting the viability of hBMSCs. DMSO can be considered a modulator of epigenetic machinery enzymes, although with milder effect compared to RG108.
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Affiliation(s)
- Rahyza I. F. Assis
- Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Malgorzata Wiench
- School of Dentistry, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Karina G. Silvério
- Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Rodrigo A. da Silva
- Department of Chemistry and Biochemistry, Biosciences Institute, São Paulo State University, Botucatu,São Paulo, Brazil
| | - Geórgia da Silva Feltran
- Department of Chemistry and Biochemistry, Biosciences Institute, São Paulo State University, Botucatu,São Paulo, Brazil
| | - Enilson A. Sallum
- Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Marcio Z. Casati
- Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Francisco H. Nociti
- Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Denise C. Andia
- Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
- Division of Epigenetics, School of Dentistry, Health Science Institute, Paulista University, São Paulo, Brazil
- * E-mail:
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22
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Gagliardi M, Strazzullo M, Matarazzo MR. DNMT3B Functions: Novel Insights From Human Disease. Front Cell Dev Biol 2018; 6:140. [PMID: 30406101 PMCID: PMC6204409 DOI: 10.3389/fcell.2018.00140] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 10/02/2018] [Indexed: 11/13/2022] Open
Abstract
DNA methylation plays important roles in gene expression regulation and chromatin structure. Its proper establishment and maintenance are essential for mammalian development and cellular differentiation. DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stage of embryonic development, including implantation. In addition to its well-known role to methylate centromeric, pericentromeric, and subtelomeric repeats, recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes. Although largely studied, much remains unknown regarding how these specific patterns of de novo CpG methylation are established in mammalian cells, and which are the rules governing DNMT3B recruitment and activity. Latest evidence indicates that DNMT3B recruitment is regulated by numerous mechanisms including chromatin modifications, transcription levels, non-coding RNAs, and the presence of DNA-binding factors. DNA methylation abnormalities are a common mark of human diseases involving chromosomal and genomic instabilities, such as inherited disease and cancer. The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene, while its altered expression has been correlated with the development of tumors. In both cases, this implies that abnormal DNA hypomethylation and hypermethylation patterns affect gene expression and genomic architecture contributing to the pathological states. We will provide an overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies.
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Affiliation(s)
- Miriam Gagliardi
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy.,Max Planck Institute of Psychiatry, Munich, Germany
| | - Maria Strazzullo
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy
| | - Maria R Matarazzo
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy
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23
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DNA methylation dynamics in aging: how far are we from understanding the mechanisms? Mech Ageing Dev 2018; 174:3-17. [DOI: 10.1016/j.mad.2017.12.002] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/14/2017] [Accepted: 12/16/2017] [Indexed: 02/07/2023]
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24
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Xu C, Corces VG. Nascent DNA methylome mapping reveals inheritance of hemimethylation at CTCF/cohesin sites. Science 2018; 359:1166-1170. [PMID: 29590048 PMCID: PMC6359960 DOI: 10.1126/science.aan5480] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 12/15/2017] [Accepted: 01/16/2018] [Indexed: 12/29/2022]
Abstract
The faithful inheritance of the epigenome is critical for cells to maintain gene expression programs and cellular identity across cell divisions. We mapped strand-specific DNA methylation after replication forks and show maintenance of the vast majority of the DNA methylome within 20 minutes of replication and inheritance of some hemimethylated CpG dinucleotides (hemiCpGs). Mapping the nascent DNA methylome targeted by each of the three DNA methyltransferases (DNMTs) reveals interactions between DNMTs and substrate daughter cytosines en route to maintenance methylation or hemimethylation. Finally, we show the inheritance of hemiCpGs at short regions flanking CCCTC-binding factor (CTCF)/cohesin binding sites in pluripotent cells. Elimination of hemimethylation causes reduced frequency of chromatin interactions emanating from these sites, suggesting a role for hemimethylation as a stable epigenetic mark regulating CTCF-mediated chromatin interactions.
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Affiliation(s)
- Chenhuan Xu
- Department of Biology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA
| | - Victor G Corces
- Department of Biology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
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25
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Hervouet E, Peixoto P, Delage-Mourroux R, Boyer-Guittaut M, Cartron PF. Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma. Clin Epigenetics 2018; 10:17. [PMID: 29449903 PMCID: PMC5807744 DOI: 10.1186/s13148-018-0450-y] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/30/2018] [Indexed: 11/28/2022] Open
Abstract
Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes. For example, the DNMT3L/DNMT3A complex is mainly related to de novo DNA methylation in embryonic states, whereas the DNMT1/PCNA/UHRF1 complex is required for maintaining global DNA methylation following DNA replication. On the opposite to these unspecific DNA methylation machineries (no preferential DNA sequence), some recently identified DNMT-including complexes are recruited on specific DNA sequences. The coexistence of both types of DNA methylation (un/specific) suggests a close cooperation and an orchestration between these systems to maintain genome and epigenome integrities. Deregulation of these systems can lead to pathologic disorders.
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Affiliation(s)
- Eric Hervouet
- INSERM unit 1098, University of Bourgogne Franche-Comté, Besançon, France.,EPIGENExp (EPIgenetics and GENe EXPression Technical Platform), Besançon, France
| | - Paul Peixoto
- INSERM unit 1098, University of Bourgogne Franche-Comté, Besançon, France.,EPIGENExp (EPIgenetics and GENe EXPression Technical Platform), Besançon, France
| | | | | | - Pierre-François Cartron
- 3INSERM unit S1232, University of Nantes, Nantes, France.,4Institut de cancérologie de l'Ouest, Nantes, France.,REpiCGO (Cancéropole Grand-Ouest), Nantes, France.,EpiSAVMEN Networks, Nantes, Région Pays de la Loire France
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26
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Ravichandran M, Jurkowska RZ, Jurkowski TP. Target specificity of mammalian DNA methylation and demethylation machinery. Org Biomol Chem 2018; 16:1419-1435. [DOI: 10.1039/c7ob02574b] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
We review here the molecular mechanisms employed by DNMTs and TET enzymes that are responsible for shaping the DNA methylation pattern of a mammalian cell.
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Affiliation(s)
| | | | - T. P. Jurkowski
- Universität Stuttgart
- Abteilung Biochemie
- Institute für Biochemie und Technische Biochemie
- Stuttgart D-70569
- Germany
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27
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Manzo M, Wirz J, Ambrosi C, Villaseñor R, Roschitzki B, Baubec T. Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands. EMBO J 2017; 36:3421-3434. [PMID: 29074627 PMCID: PMC5709737 DOI: 10.15252/embj.201797038] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 10/01/2017] [Accepted: 10/03/2017] [Indexed: 01/14/2023] Open
Abstract
DNA methylation is a prevalent epigenetic modification involved in transcriptional regulation and essential for mammalian development. While the genome-wide distribution of this mark has been studied to great detail, the mechanisms responsible for its correct deposition, as well as the cause for its aberrant localization in cancers, have not been fully elucidated. Here, we have compared the activity of individual DNMT3A isoforms in mouse embryonic stem and neuronal progenitor cells and report that these isoforms differ in their genomic binding and DNA methylation activity at regulatory sites. We identify that the longer isoform DNMT3A1 preferentially localizes to the methylated shores of bivalent CpG island promoters in a tissue-specific manner. The isoform-specific targeting of DNMT3A1 coincides with elevated hydroxymethylcytosine (5-hmC) deposition, suggesting an involvement of this isoform in mediating turnover of DNA methylation at these sites. Through genetic deletion and rescue experiments, we demonstrate that this isoform-specific recruitment plays a role in de novo DNA methylation at CpG island shores, with potential implications on H3K27me3-mediated regulation of developmental genes.
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Affiliation(s)
- Massimiliano Manzo
- Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.,Molecular Life Sciences, PhD Program of the Life Sciences, Zurich Graduate School, University of Zurich, Zurich, Switzerland
| | - Joël Wirz
- Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland
| | - Christina Ambrosi
- Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.,Molecular Life Sciences, PhD Program of the Life Sciences, Zurich Graduate School, University of Zurich, Zurich, Switzerland
| | - Rodrigo Villaseñor
- Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland
| | - Bernd Roschitzki
- Functional Genomics Center Zurich, ETH and University of Zurich, Zurich, Switzerland
| | - Tuncay Baubec
- Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland
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28
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Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets. Genes (Basel) 2017; 8:genes8080196. [PMID: 28783137 PMCID: PMC5575660 DOI: 10.3390/genes8080196] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/19/2017] [Accepted: 07/31/2017] [Indexed: 12/19/2022] Open
Abstract
The nucleosome surface is covered with multiple modifications that are perpetuated by eight different classes of enzymes. These enzymes modify specific target sites both on DNA and histone proteins, and these modifications have been well identified and termed “epigenetics”. These modifications play critical roles, either by affecting non-histone protein recruitment to chromatin or by disturbing chromatin contacts. Their presence dictates the condensed packaging of DNA and can coordinate the orderly recruitment of various enzyme complexes for DNA manipulation. This genetic modification machinery involves various writers, readers, and erasers that have unique structures, functions, and modes of action. Regarding human disease, studies have mainly focused on the genetic mechanisms; however, alteration in the balance of epigenetic networks can result in major pathologies including mental retardation, chromosome instability syndromes, and various types of cancers. Owing to its critical influence, great potential lies in developing epigenetic therapies. In this regard, this review has highlighted mechanistic and structural interactions of the main epigenetic families with their targets, which will help to identify more efficient and safe drugs against several diseases.
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29
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Velazquez Camacho O, Galan C, Swist-Rosowska K, Ching R, Gamalinda M, Karabiber F, De La Rosa-Velazquez I, Engist B, Koschorz B, Shukeir N, Onishi-Seebacher M, van de Nobelen S, Jenuwein T. Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation. eLife 2017; 6. [PMID: 28760199 PMCID: PMC5538826 DOI: 10.7554/elife.25293] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 06/09/2017] [Indexed: 12/19/2022] Open
Abstract
The Suv39h1 and Suv39h2 histone lysine methyltransferases are hallmark enzymes at mammalian heterochromatin. We show here that the mouse Suv39h2 enzyme differs from Suv39h1 by containing an N-terminal basic domain that facilitates retention at mitotic chromatin and provides an additional affinity for major satellite repeat RNA. To analyze an RNA-dependent interaction with chromatin, we purified native nucleosomes from mouse ES cells and detect that Suv39h1 and Suv39h2 exclusively associate with poly-nucleosomes. This association was attenuated upon RNaseH incubation and entirely lost upon RNaseA digestion of native chromatin. Major satellite repeat transcripts remain chromatin-associated and have a secondary structure that favors RNA:DNA hybrid formation. Together, these data reveal an RNA-mediated mechanism for the stable chromatin interaction of the Suv39h KMT and suggest a function for major satellite non-coding RNA in the organization of an RNA-nucleosome scaffold as the underlying structure of mouse heterochromatin.
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Affiliation(s)
- Oscar Velazquez Camacho
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology, Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Carmen Galan
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Kalina Swist-Rosowska
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology, Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Reagan Ching
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Michael Gamalinda
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | | | | | - Bettina Engist
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Birgit Koschorz
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Nicholas Shukeir
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | | | | | - Thomas Jenuwein
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
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30
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Human DNA (cytosine-5)-methyltransferases: a functional and structural perspective for epigenetic cancer therapy. Biochimie 2017; 139:137-147. [DOI: 10.1016/j.biochi.2017.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 06/04/2017] [Indexed: 01/06/2023]
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31
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Bajpeyi S, Covington JD, Taylor EM, Stewart LK, Galgani JE, Henagan TM. Skeletal Muscle PGC1α -1 Nucleosome Position and -260 nt DNA Methylation Determine Exercise Response and Prevent Ectopic Lipid Accumulation in Men. Endocrinology 2017; 158:2190-2199. [PMID: 28398573 PMCID: PMC5505213 DOI: 10.1210/en.2017-00051] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 04/04/2017] [Indexed: 01/13/2023]
Abstract
Endurance exercise has been shown to improve lipid oxidation and increase mitochondrial content in skeletal muscle, two features that have shown dependence on increased expression of the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α). It is also hypothesized that exercise-related alterations in PGC1α expression occur through epigenetic regulation of nucleosome positioning in association with differential DNA methylation status within the PGC1α promoter. In this study, we show that when primary human myotubes from obese patients with type 2 diabetes are exposed to lipolytic stimulus (palmitate, forskolin, inomycin) in vitro, nucleosome occupancy surrounding the -260 nucleotide (nt) region, a known regulatory DNA methylation site, is reduced. This finding is reproduced in vivo in the vastus lateralis from 11 healthy males after a single, long endurance exercise bout in which participants expended 650 kcal. Additionally, we show a significant positive correlation between fold change of PGC1α messenger RNA expression and -1 nucleosome repositioning away from the -260 nt methylation site in skeletal muscle tissue following exercise. Finally, we found that when exercise participants are divided into high and low responders based on the -260 nt methylation status, the -1 nucleosome is repositioned away from the regulatory -260 nt methylation site in high responders, those exhibiting a significant decrease in -260 nt methylation, but not in low responders. Additionally, high but not low responders showed a significant decrease in intramyocellular lipid content after exercise. These findings suggest a potential target for epigenetic modification of the PGC1α promoter to stimulate the therapeutic effects of endurance exercise in skeletal muscle.
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Affiliation(s)
- Sudip Bajpeyi
- Department of Kinesiology, University of Texas at El Paso, El Paso, Texas 79968
| | - Jeffrey D. Covington
- Laboratory of Skeletal Muscle Physiology, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808
- School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112
| | - Erin M. Taylor
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47907
| | - Laura K. Stewart
- Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado 80639
| | - Jose E. Galgani
- Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
| | - Tara M. Henagan
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47907
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32
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Smets M, Link S, Wolf P, Schneider K, Solis V, Ryan J, Meilinger D, Qin W, Leonhardt H. DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation. Hum Mol Genet 2017; 26:1522-1534. [PMID: 28334952 PMCID: PMC5393148 DOI: 10.1093/hmg/ddx057] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 02/09/2017] [Indexed: 12/26/2022] Open
Abstract
DNMT1 is recruited to substrate sites by PCNA and UHRF1 to maintain DNA methylation after replication. The cell cycle dependent recruitment of DNMT1 is mediated by the PCNA-binding domain (PBD) and the targeting sequence (TS) within the N-terminal regulatory domain. The TS domain was found to be mutated in patients suffering from hereditary sensory and autonomic neuropathies with dementia and hearing loss (HSANIE) and autosomal dominant cerebellar ataxia deafness and narcolepsy (ADCA-DN) and is associated with global hypomethylation and site specific hypermethylation. With functional complementation assays in mouse embryonic stem cells, we showed that DNMT1 mutations P496Y and Y500C identified in HSANIE patients not only impair DNMT1 heterochromatin association, but also UHRF1 interaction resulting in hypomethylation. Similar DNA methylation defects were observed when DNMT1 interacting domains in UHRF1, the UBL and the SRA domain, were deleted. With cell-based assays, we could show that HSANIE associated mutations perturb DNMT1 heterochromatin association and catalytic complex formation at methylation sites and decrease protein stability in late S and G2 phase. To investigate the neuronal phenotype of HSANIE mutations, we performed DNMT1 rescue assays and could show that cells expressing mutated DNMT1 were prone to apoptosis and failed to differentiate into neuronal lineage. Our results provide insights into the molecular basis of DNMT1 dysfunction in HSANIE patients and emphasize the importance of the TS domain in the regulation of DNA methylation in pluripotent and differentiating cells.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Heinrich Leonhardt
- To whom correspondence should be addressed. Tel: +49 89 218074232; Fax: +49 89 218074236;
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33
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He CC, Wang ZY, Tian K, Liu W, Li YB, Hong Y, Yu LX, Pang W, Jiang YG, Liu YQ. DNA methylation mechanism of intracellular zinc deficiency-induced injury in primary hippocampal neurons in the rat brain. Nutr Neurosci 2017; 21:478-486. [DOI: 10.1080/1028415x.2017.1312090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Cong-cong He
- College of Life Sciences, Nankai University, Tianjin 300071, China
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Zi-yu Wang
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Kun Tian
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Wei Liu
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Yi-bo Li
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Yan Hong
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Li-xia Yu
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Wei Pang
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Yu-gang Jiang
- Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China
| | - Yan-qiang Liu
- College of Life Sciences, Nankai University, Tianjin 300071, China
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Ratovitski EA. Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression. Curr Genomics 2017; 18:175-205. [PMID: 28367075 PMCID: PMC5345332 DOI: 10.2174/1389202917666160803165229] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 11/24/2015] [Accepted: 11/29/2015] [Indexed: 11/30/2022] Open
Abstract
Accumulating evidence shows that hallmarks of cancer include: "genetic and epigenetic alterations leading to inactivation of cancer suppressors, overexpression of oncogenes, deregulation of intracellular signaling cascades, alterations of cancer cell metabolism, failure to undergo cancer cell death, induction of epithelial to mesenchymal transition, invasiveness, metastasis, deregulation of immune response and changes in cancer microenvironment, which underpin cancer development". Natural compounds as bioactive ingredients isolated from natural sources (plants, fungi, marine life forms) have revolutionized the field of anticancer therapeutics and rapid developments in preclinical studies are encouraging. Natural compounds could affect the epigenetic molecular mechanisms that modulate gene expression, as well as DNA damage and repair mechanisms. The current review will describe the latest achievements in using naturally produced compounds targeting epigenetic regulators and modulators of gene transcription in vitro and in vivo to generate novel anticancer therapeutics.
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Affiliation(s)
- Edward A. Ratovitski
- Head and Neck Cancer Research Division, Department of Otolaryngology/Head and Neck Surgery, The Johns Hopkins School of Medicine, Baltimore, MD 21231, USA
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35
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Liang G, Weisenberger DJ. DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. Epigenetics 2017; 12:416-432. [PMID: 28358281 DOI: 10.1080/15592294.2017.1311434] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
DNA methylation aberrancies are hallmarks of human cancers and are characterized by global DNA hypomethylation of repetitive elements and non-CpG rich regions concomitant with locus-specific DNA hypermethylation. DNA methylation changes may result in altered gene expression profiles, most notably the silencing of tumor suppressors, microRNAs, endogenous retorviruses and tumor antigens due to promoter DNA hypermethylation, as well as oncogene upregulation due to gene-body DNA hypermethylation. Here, we review DNA methylation aberrancies in human cancers, their use in cancer surveillance and the interplay between DNA methylation and histone modifications in gene regulation. We also summarize DNA methylation inhibitors and their therapeutic effects in cancer treatment. In this context, we describe the integration of DNA methylation inhibitors with conventional chemotherapies, DNA repair inhibitors and immune-based therapies, to bring the epigenome closer to its normal state and increase sensitivity to other therapeutic agents to improve patient outcome and survival.
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Affiliation(s)
- Gangning Liang
- a Department of Urology , University of Southern California, USC Norris Comprehensive Cancer Center , Los Angeles , CA , USA
| | - Daniel J Weisenberger
- b Department of Biochemistry and Molecular Medicine , University of Southern California, USC Norris Comprehensive Cancer Center , Los Angeles , CA , USA
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36
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Ambrosi C, Manzo M, Baubec T. Dynamics and Context-Dependent Roles of DNA Methylation. J Mol Biol 2017; 429:1459-1475. [PMID: 28214512 DOI: 10.1016/j.jmb.2017.02.008] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Revised: 01/26/2017] [Accepted: 02/09/2017] [Indexed: 12/22/2022]
Abstract
DNA methylation is one of the most extensively studied epigenetic marks. It is involved in transcriptional gene silencing and plays important roles during mammalian development. Its perturbation is often associated with human diseases. In mammalian genomes, DNA methylation is a prevalent modification that decorates the majority of cytosines. It is found at the promoters and enhancers of inactive genes, at repetitive elements, and within transcribed gene bodies. Its presence at promoters is dynamically linked to gene activity, suggesting that it could directly influence gene expression patterns and cellular identity. The genome-wide distribution and dynamic behaviour of this mark have been studied in great detail in a variety of tissues and cell lines, including early embryonic development and in embryonic stem cells. In combination with functional studies, these genome-wide maps of DNA methylation revealed interesting features of this mark and provided important insights into its dynamic nature and potential functional role in genome regulation. In this review, we discuss how these recent observations, in combination with insights obtained from biochemical and functional genetics studies, have expanded our current knowledge about the regulation and context-dependent roles of DNA methylation in mammalian genomes.
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Affiliation(s)
- Christina Ambrosi
- Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Molecular Life Sciences PhD Program of the Life Sciences Zurich Graduate School, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Massimiliano Manzo
- Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Molecular Life Sciences PhD Program of the Life Sciences Zurich Graduate School, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Tuncay Baubec
- Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
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Helbo AS, Lay FD, Jones PA, Liang G, Grønbæk K. Nucleosome Positioning and NDR Structure at RNA Polymerase III Promoters. Sci Rep 2017; 7:41947. [PMID: 28176797 PMCID: PMC5296907 DOI: 10.1038/srep41947] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 01/03/2017] [Indexed: 12/20/2022] Open
Abstract
Chromatin is structurally involved in the transcriptional regulation of all genes. While the nucleosome positioning at RNA polymerase II (pol II) promoters has been extensively studied, less is known about the chromatin structure at pol III promoters in human cells. We use a high-resolution analysis to show substantial differences in chromatin structure of pol II and pol III promoters, and between subtypes of pol III genes. Notably, the nucleosome depleted region at the transcription start site of pol III genes extends past the termination sequences, resulting in nucleosome free gene bodies. The +1 nucleosome is located further downstream than at pol II genes and furthermore displays weak positioning. The variable position of the +1 location is seen not only within individual cell populations and between cell types, but also between different pol III promoter subtypes, suggesting that the +1 nucleosome may be involved in the transcriptional regulation of pol III genes. We find that expression and DNA methylation patterns correlate with distinct accessibility patterns, where DNA methylation associates with the silencing and inaccessibility at promoters. Taken together, this study provides the first high-resolution map of nucleosome positioning and occupancy at human pol III promoters at specific loci and genome wide.
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Affiliation(s)
- Alexandra Søgaard Helbo
- Department of Hematology, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, 2100, Denmark
| | - Fides D Lay
- Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90089, USA
| | - Peter A Jones
- Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90089, USA.,Van Andel Research Institute, Grand Rapids, 49503, USA
| | - Gangning Liang
- Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90089, USA
| | - Kirsten Grønbæk
- Department of Hematology, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, 2100, Denmark
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38
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Zhan Y, Guo Y, Lu Q. Aberrant Epigenetic Regulation in the Pathogenesis of Systemic Lupus Erythematosus and Its Implication in Precision Medicine. Cytogenet Genome Res 2016; 149:141-155. [PMID: 27607472 DOI: 10.1159/000448793] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2016] [Indexed: 11/19/2022] Open
Abstract
Great progress has been made in the last decades in understanding the complex immune dysregulation in systemic lupus erythematosus (SLE), yet the efforts to pursue an effective treatment of SLE proved to be futile. The pathoetiology of SLE involves extremely complicated and multifactorial interaction among various genetic and epigenetic factors. Multiple gene loci predispose to disease susceptibility, and the interaction with epigenetic modifications mediated through sex, hormones, and the hypothalamo-pituitary-adrenal axis complicates susceptibility and manifestations of this disease. Finally, certain environmental and psychological factors probably trigger the disease via epigenetic mechanisms. In this review, we summarize and discuss recent epigenetic studies of SLE and suggest a personalized approach to the dissection of disease onset and therapy or precision medicine. We speculate that in the future, precision medicine based on epigenetic and genetic information could help guide more effective targeted therapeutic intervention.
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Affiliation(s)
- Yi Zhan
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, PR China
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39
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Cree SL, Fredericks R, Miller A, Pearce FG, Filichev V, Fee C, Kennedy MA. DNA G-quadruplexes show strong interaction with DNA methyltransferases in vitro. FEBS Lett 2016; 590:2870-83. [PMID: 27468168 DOI: 10.1002/1873-3468.12331] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 07/07/2016] [Accepted: 07/21/2016] [Indexed: 12/16/2022]
Abstract
The DNA methyltransferase enzymes (DNMTs) catalyzing cytosine methylation do so at specific locations of the genome, although with some level of redundancy. The de novo methyltransferases DNMT3A and 3B play a vital role in methylating the genome of the developing embryo in regions devoid of methylation marks. The ability of DNMTs to colocalize at sites of DNA damage is suggestive that recognition of mispaired bases and unusual structures is inherent to the function of these proteins. We provide evidence for G-quadruplex formation within imprinted gene promoters, and report high-affinity binding of recombinant human DNMTs to such DNA G-quadruplexes in vitro. These observations suggest a potential interaction of G-quadruplexes with the DNA methylation machinery, which may be of epigenetic and biological significance.
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Affiliation(s)
- Simone L Cree
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Rayleen Fredericks
- Department of Chemical and Process Engineering, University of Canterbury, Christchurch, New Zealand
- Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand
| | - Allison Miller
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - F Grant Pearce
- Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand
- School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
| | - Vyacheslav Filichev
- Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand
| | - Conan Fee
- Department of Chemical and Process Engineering, University of Canterbury, Christchurch, New Zealand
- Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand
| | - Martin A Kennedy
- Department of Pathology, University of Otago, Christchurch, New Zealand
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40
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Jeltsch A, Jurkowska RZ. Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm. Nucleic Acids Res 2016; 44:8556-8575. [PMID: 27521372 PMCID: PMC5062992 DOI: 10.1093/nar/gkw723] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 08/08/2016] [Indexed: 12/23/2022] Open
Abstract
In mammals, DNA methylation is introduced by the DNMT1, DNMT3A and DNMT3B methyltransferases, which are all large multi-domain proteins containing a catalytic C-terminal domain and an N-terminal part with regulatory functions. Recently, two novel regulatory principles of DNMTs were uncovered. It was shown that their catalytic activity is under allosteric control of N-terminal domains with autoinhibitory function, the RFT and CXXC domains in DNMT1 and the ADD domain in DNMT3. Moreover, targeting and activity of DNMTs were found to be regulated in a concerted manner by interactors and posttranslational modifications (PTMs). In this review, we describe the structures and domain composition of the DNMT1 and DNMT3 enzymes, their DNA binding, catalytic mechanism, multimerization and the processes controlling their stability in cells with a focus on their regulation and chromatin targeting by PTMs, interactors and chromatin modifications. We propose that the allosteric regulation of DNMTs by autoinhibitory domains acts as a general switch for the modulation of the function of DNMTs, providing numerous possibilities for interacting proteins, nucleic acids or PTMs to regulate DNMT activity and targeting. The combined regulation of DNMT targeting and catalytic activity contributes to the precise spatiotemporal control of DNMT function and genome methylation in cells.
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Affiliation(s)
- Albert Jeltsch
- Institute of Biochemistry, Pfaffenwaldring 55, Faculty of Chemistry, University of Stuttgart, D-70569 Stuttgart, Germany
| | - Renata Z Jurkowska
- BioMed X Innovation Center, Im Neuenheimer Feld 583, D-69120 Heidelberg, Germany
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41
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Sneppen K, Dodd IB. Nucleosome dynamics and maintenance of epigenetic states of CpG islands. Phys Rev E 2016; 93:062417. [PMID: 27415308 DOI: 10.1103/physreve.93.062417] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Indexed: 01/02/2023]
Abstract
Methylation of mammalian DNA occurs primarily at CG dinucleotides. These CpG sites are located nonrandomly in the genome, tending to occur within high density clusters of CpGs (islands) or within large regions of low CpG density. Cluster methylation tends to be bimodal, being dominantly unmethylated or mostly methylated. For CpG clusters near promoters, low methylation is associated with transcriptional activity, while high methylation is associated with gene silencing. Alternative CpG methylation states are thought to be stable and heritable, conferring localized epigenetic memory that allows transient signals to create long-lived gene expression states. Positive feedback where methylated CpG sites recruit enzymes that methylate nearby CpGs, can produce heritable bistability but does not easily explain that as clusters increase in size or density they change from being primarily methylated to primarily unmethylated. Here, we show that an interaction between the methylation state of a cluster and its occupancy by nucleosomes provides a mechanism to generate these features and explain genome wide systematics of CpG islands.
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Affiliation(s)
- Kim Sneppen
- Center for Models of Life, Niels Bohr Institute, Blegdamsvej 17, 2100 Copenhagen, Denmark
| | - Ian B Dodd
- Department of Molecular and Cellular Biology, University of Adelaide, Adelaide SA 5005, Australia
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42
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Rondelet G, Dal Maso T, Willems L, Wouters J. Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B. J Struct Biol 2016; 194:357-67. [PMID: 26993463 DOI: 10.1016/j.jsb.2016.03.013] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 03/14/2016] [Accepted: 03/15/2016] [Indexed: 01/01/2023]
Abstract
DNA methylation is an important epigenetic modification involved in chromatin organization and gene expression. The function of DNA methylation depends on cell context and is correlated with histone modification patterns. In particular, trimethylation of Lys36 on histone H3 tail (H3K36me3) is associated with DNA methylation and elongation phase of transcription. PWWP domains of the de novo DNA methyltransferases DNMT3A and DNMT3B read this epigenetic mark to guide DNA methylation. Here we report the first crystal structure of the DNMT3B PWWP domain-H3K36me3 complex. Based on this structure, we propose a model of the DNMT3A PWWP domain-H3K36me3 complex and build a model of DNMT3A (PWWP-ADD-CD) in a nucleosomal context. The trimethylated side chain of Lys36 (H3K36me3) is inserted into an aromatic cage similar to the "Royal" superfamily domains known to bind methylated histones. A key interaction between trimethylated Lys36 and a conserved water molecule stabilized by Ser270 explains the lack of affinity of mutated DNMT3B (S270P) for the H3K36me3 epigenetic mark in the ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome. The model of the DNMT3A-DNMT3L heterotetramer in complex with a dinucleosome highlights the mechanism for recognition of nucleosome by DNMT3s and explains the periodicity of de novo DNA methylation.
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Affiliation(s)
- Grégoire Rondelet
- Department of Chemistry, University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium.
| | - Thomas Dal Maso
- Department of Chemistry, University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium
| | - Luc Willems
- Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (Gembloux Agro-Bio Tech), University of Liège (ULg), 4000 Liège, Belgium
| | - Johan Wouters
- Department of Chemistry, University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium
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43
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Duymich CE, Charlet J, Yang X, Jones PA, Liang G. DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells. Nat Commun 2016; 7:11453. [PMID: 27121154 PMCID: PMC4853477 DOI: 10.1038/ncomms11453] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 03/30/2016] [Indexed: 01/08/2023] Open
Abstract
Promoter DNA methylation is a key epigenetic mechanism for stable gene silencing, but is correlated with expression when located in gene bodies. Maintenance and de novo DNA methylation by catalytically active DNA methyltransferases (DNMT1 and DNMT3A/B) require accessory proteins such as UHRF1 and DNMT3L. DNMT3B isoforms are widely expressed, although some do not have active catalytic domains and their expression can be altered during cell development and tumourigenesis, questioning their biological roles. Here, we show that DNMT3B isoforms stimulate gene body methylation and re-methylation after methylation-inhibitor treatment. This occurs independently of the isoforms' catalytic activity, demonstrating a similar functional role to the accessory protein DNMT3L, which is only expressed in undifferentiated cells and recruits DNMT3A to initiate DNA methylation. This unexpected role for DNMT3B suggests that it might substitute for the absent accessory protein DNMT3L to recruit DNMT3A in somatic cells.
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Affiliation(s)
- Christopher E. Duymich
- Department of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
| | - Jessica Charlet
- Department of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
| | - Xiaojing Yang
- Department of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
| | - Peter A. Jones
- Department of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
| | - Gangning Liang
- Department of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
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44
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Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer. Cell Discov 2016; 2:16007. [PMID: 27462454 PMCID: PMC4849474 DOI: 10.1038/celldisc.2016.7] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 01/29/2016] [Indexed: 12/19/2022] Open
Abstract
Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A.
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45
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Cui Y, Choudhury SR, Irudayaraj J. Epigenetic Toxicity of Trichloroethylene: A Single-Molecule Perspective. Toxicol Res (Camb) 2016; 5:641-650. [PMID: 28944004 DOI: 10.1039/c5tx00454c] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The volatile, water soluble trichloroethylene (TCE) is a hazardous industrial waste and could lead to various health problems, including cancer, neuropathy, cardiovascular defects, and immune diseases. Toxicological studies taking use of in vitro and in vivo models have been conducted to understand the biological impacts of TCE at the genetic, transcriptomic, metabolomic, and signaling levels. The epigenetic aberrations induced by TCE have also been reported in a number of model organisms, while a detailed mechanistic elucidation is lacking. In this study we uncover an unreported mechanism accounting for the epigenetic toxicity due to TCE exposure by monitoring the single-molecule dynamics of DNA methyltransferase 3a (Dnmt3a) in living cells. TCE-induced global DNA hypomethylation could be partly attributed to the disrupted Dnmt3a-DNA association. By analyzing the components of detached Dnmt3a, we found that the Dnmt3a oligomers (e.g., dimer, trimer, and high-order oligomers) dissociated from heterochromatin in a dose-dependent manner upon exposure. Thereafter the diminished DNA-binding affinity of Dnmt3a resulted in a significant decrease in 5-methylcytosine (5mC) under both acute high-dosage and chronic low-dosage TCE exposure. The resulting DNA demethylation might also be contributed by the elevated expression of ten-eleven-translocation (Tet) enzymes and reformed cysteine cycle. Besides the global effect, we further identified that a group of heterochromatin-located, cancer-related microRNAs (miRNAs) experienced promoter demethylation upon TCE exposure.
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Affiliation(s)
- Yi Cui
- Department of Agricultural and Biological Engineering, Bindley Bioscience Center, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
| | - Samrat Roy Choudhury
- Department of Agricultural and Biological Engineering, Bindley Bioscience Center, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
| | - Joseph Irudayaraj
- Department of Agricultural and Biological Engineering, Bindley Bioscience Center, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
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46
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Jurkowska RZ, Jeltsch A. Enzymology of Mammalian DNA Methyltransferases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 945:87-122. [PMID: 27826836 DOI: 10.1007/978-3-319-43624-1_5] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
DNA methylation is currently one of the hottest topics in basic and biomedical research. Despite tremendous progress in understanding the structures and biochemical properties of the mammalian DNA nucleotide methyltransferases (DNMTs), principles of their regulation in cells have only begun to be uncovered. In mammals, DNA methylation is introduced by the DNMT1, DNMT3A, and DNMT3B enzymes, which are all large multi-domain proteins. These enzymes contain a catalytic C-terminal domain with a characteristic cytosine-C5 methyltransferase fold and an N-terminal part with different domains that interacts with other proteins and chromatin and is involved in targeting and regulation of the DNMTs. The subnuclear localization of the DNMT enzymes plays an important role in their biological function: DNMT1 is localized to replicating DNA via interaction with PCNA and UHRF1. DNMT3 enzymes bind to heterochromatin via protein multimerization and are targeted to chromatin by their ADD and PWWP domains. Recently, a novel regulatory mechanism has been discovered in DNMTs, as latest structural and functional data demonstrated that the catalytic activities of all three enzymes are under tight allosteric control of their N-terminal domains having autoinhibitory functions. This mechanism provides numerous possibilities for the precise regulation of the methyltransferases via controlling the binding and release of autoinhibitory domains by protein factors, noncoding RNAs, or by posttranslational modifications of the DNMTs. In this chapter, we summarize key enzymatic properties of DNMTs, including their specificity and processivity, and afterward we focus on the regulation of their activity and targeting via allosteric processes, protein interactors, and posttranslational modifications.
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Affiliation(s)
- Renata Z Jurkowska
- BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg, D-69120, Germany.
| | - Albert Jeltsch
- Institute of Biochemistry, Faculty of Chemistry, University of Stuttgart, Pfaffenwaldring 55, Stuttgart, D-70569, Germany.
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47
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Sanchez-Mut JV, Gräff J. Epigenetic Alterations in Alzheimer's Disease. Front Behav Neurosci 2015; 9:347. [PMID: 26734709 PMCID: PMC4681781 DOI: 10.3389/fnbeh.2015.00347] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 11/25/2015] [Indexed: 12/11/2022] Open
Abstract
Alzheimer’s disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.
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Affiliation(s)
- Jose V Sanchez-Mut
- Neuroepigenetics Laboratory - UPGRAEFF, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne Lausanne, Switzerland
| | - Johannes Gräff
- Neuroepigenetics Laboratory - UPGRAEFF, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne Lausanne, Switzerland
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48
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Minarovits J, Demcsák A, Banati F, Niller HH. Epigenetic Dysregulation in Virus-Associated Neoplasms. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 879:71-90. [DOI: 10.1007/978-3-319-24738-0_4] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Nishiyama A, Yamaguchi L, Nakanishi M. Regulation of maintenance DNA methylation via histone ubiquitylation. J Biochem 2015; 159:9-15. [PMID: 26590302 DOI: 10.1093/jb/mvv113] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 10/07/2015] [Indexed: 11/13/2022] Open
Abstract
DNA methylation is one of the most stable but dynamically regulated epigenetic marks that act as determinants of cell fates during embryonic development through regulation of various forms of gene expression. DNA methylation patterns must be faithfully propagated throughout successive cell divisions in order to maintain cell-specific function. We have recently demonstrated that Uhrf1-dependent ubiquitylation of histone H3 at lysine 23 is critical for Dnmt1 recruitment to DNA replication sites, which catalyzes the conversion of hemi-methylated DNA to fully methylated DNA. In this review, we provide an overview of recent progress in understanding the mechanism underlying maintenance DNA methylation.
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Affiliation(s)
- Atsuya Nishiyama
- Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Luna Yamaguchi
- Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Makoto Nakanishi
- Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
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Cañas CA, Cañas F, Bonilla-Abadía F, Ospina FE, Tobón GJ. Epigenetics changes associated to environmental triggers in autoimmunity. Autoimmunity 2015; 49:1-11. [PMID: 26369426 DOI: 10.3109/08916934.2015.1086996] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Autoimmune diseases (AIDs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens and represent a heterogeneous group of disorders that affect specific target organs or multiple organs in different systems. While the pathogenesis of AID remains unclear, its aetiology is multifunctional and includes a combination of genetic, epigenetic, immunological and environmental factors. In AIDs, several epigenetic mechanisms are defective including DNA demethylation, abnormal chromatin positioning associated with autoantibody production and abnormalities in the expression of RNA interference (RNAi). It is known that environmental factors may interfere with DNA methylation and histone modifications, however, little is known about epigenetic changes derived of regulation of RNAi. An approach to the known environmental factors and the mechanisms that alter the epigenetic regulation in AIDs (with emphasis in systemic lupus erythematosus, the prototype of systemic AID) are showed in this review.
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Affiliation(s)
- Carlos A Cañas
- a Department of Internal Medicine, Division of Rheumatology , Fundación Valle del Lili , Cali , Colombia and
| | - Felipe Cañas
- b Department of Internal Medicine, Fundación Valle del Lili, Cali , CES University School of Medicine , Medellín, Cali , Colombia
| | - Fabio Bonilla-Abadía
- a Department of Internal Medicine, Division of Rheumatology , Fundación Valle del Lili , Cali , Colombia and
| | - Fabio E Ospina
- a Department of Internal Medicine, Division of Rheumatology , Fundación Valle del Lili , Cali , Colombia and
| | - Gabriel J Tobón
- a Department of Internal Medicine, Division of Rheumatology , Fundación Valle del Lili , Cali , Colombia and
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