DOCSLIB.ORG

Hbx Induces Hypomethylation of Distal Intragenic Cpg Islands Required for Active Expression of Developmental Regulators

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hbx Induces Hypomethylation of Distal Intragenic Cpg Islands Required for Active Expression of Developmental Regulators HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators Sun-Min Leea, Young-gun Leeb, Jae-Bum Baea,1, Jung Kyoon Choia,2, Chiharu Tayamac, Kenichiro Hatac, Yungdae Yund, Je-Kyung Seonge, and Young-Joon Kima,b,3 aDepartment of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 120-749, Korea; bDepartment of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea; cDepartment of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; dDepartment of Life Science and the Center for Cellular Homeostasis, Ewha Woman’s University of Life Science, Seoul 120-750, Korea; and eLaboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea Edited* by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, and approved May 19, 2014 (received for review January 13, 2014) Epigenetic alterations caused by viral oncoproteins are strong Some unmethylated intragenic and intergenic CGIs contain distinct initiation factors for cancer development, but their mechanisms epigenetic markers and work as enhancers or alternative promoters, are largely unknown. To identify the epigenetic effects of viral demonstrating the regulatory potential of CGIs. Although most hepatitis B virus X (HBx) that lead to hepatocellular carcinoma (HCC), promoter associate CGIs are unmethylated, about 20–30% of CGIs we profiled the DNA methylomes of normal and HBx transgenic found in the gene body are highly methylated (13) and suggested as mouse liver. Intriguingly, severe hypomethylation of intragenic CpG marking actively transcribed regions (14) or as suppressing pro- islands (CGIs) was observed in HBx liver before the full development moters for antisense transcripts (15). of HCC. Normally, these CGIs were highly methylated (mCGIs) by the The HBV x (HBx) protein, which plays a critical role in the DNMT3L complex and marked with epigenetic signatures associated development of HCC, was shown to interact with several epi- with active expression, such as H3K36me3. Hypomethylation of genetic factors, such as DNMT3A and HDAC1 (16). However, mCGI was caused by the downregulation of Dnmt3L and Dnmt3a the physiological significance of these interactions and the reg- due to HBx bound to their promoters, along with HDAC1. These ulatory mechanism leading to gene silencing are not clear. HBx events lead to the downregulation of many developmental regu- was shown to recruit DNMT3A to certain promoters to repress lators that could facilitate tumorigenesis. Here we provide an their activities through de novo DNA methylation; however, intriguing epigenetic regulation mediated by mCGI that is required HBx also causes hypomethylation in certain promoters, possibly via the redistribution of DNMT3A to other promoters (16). In for cell differentiation and describe a previously unidentified epige- netic role for HBx in promoting HCC development. Significance DNA methylation | methylated CpG island | viral protein Epigenetic dysregulation by oncoviral protein plays a key role epatocellular carcinoma (HCC) is one of the most danger- in tumor development. DNA methylome analysis of hepatitis B Hous cancers that threaten many people, especially those with virus X (HBx)-induced hepatocellular carcinoma (HCC) revealed hepatitis B or C virus (HBV or HCV) (1–3). However, the exact drastic changes in host epigenome, but in an unconventional mechanisms underlying HCC are not clear because there are way: intragenic CpG islands (CGIs) were dramatically deme- multiple factors, including chronic inflammation (4), genetic al- thylated. We showed methylated intragenic CGIs as previously teration caused by viral integration into the host genome (5), and unidentified regulatory elements associated with active ex- pression. The methylated CGIs are marked with distinct epi- the oncogenic actions of viral proteins (6). Although many genetic signatures and require DNA methyltransferase (DNMT) studies have previously demonstrated that these factors, alone or 3L complex for their high methylation levels. By directly sup- in combination with other factors, are able to initiate tumori- pressing Dnmt3L and Dnmt3a promoters, HBx induces hypo- genesis (1), the oncogenic potential of viral protein in cancer methylation of the intragenic CGIs and downregulation of the development is one of the most interesting exogenic factors that associated developmental regulators. We provide previously facilitates tumorigenesis, in particular, through the epigenetic unreported functional identification of intragenic CGIs that regulation of infected cells (7). may enhance our understanding of epigenetic regulation and Epigenetic alterations in cancer cells are now regarded as one a new epigenetic role for HBx in promoting HCC development. of the most important factors driving cancer initiation. Abnormal DNA methylation is the most frequently found change in many Author contributions: S.-M.L. and Y.-J.K. designed research; S.-M.L. and J.-B.B. performed cancers and is believed to control associated gene expression research; Y.-g.L., J.K.C., C.T., K.H., Y.Y., and J.-K.S. contributed new reagents/analytic without altering the DNA sequence itself (8). The transcriptional tools; S.-M.L. analyzed data; and S.-M.L. and Y.-J.K. wrote the paper. silencing of tumor suppressor genes associated with the hyper- The authors declare no conflict of interest. methylation of promoter regions is a typical epigenetic change *This Direct Submission article had a prearranged editor. in many cancers (9). The DNA hypomethylation in repeat se- Data deposition: The sequences reported in this paper have been deposited in the Gene quences and transposable elements is known to induce chromo- Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. somal instability and mutation events (10) that lead to cancer GSE48052). development and progression (11). In addition, various types 1Present address: Division of Structural and Functional Genomics, Center for Genome of cancer cells exhibit abnormal expression levels of DNA methyl- Science, Korea National Institute of Health, Osongsaemyeong 2-ro, Osong-eup, transferase (DNMT) families, which probably causes global Cheongwon-gun, Chungcheongbuk-do 363-700, Korea. changes in DNA methylation (12). 2Present address: Department of Bio and Brain Engineering, Korea Advanced Institute of In mammalian cells, large clusters of CpG dinucleotides Science and Technology, Daejeon 305-701, Korea. 3 known as CpG islands (CGIs) appear to act as a key epigenetic To whom correspondence should be addressed. E-mail: [email protected]. GENETICS element regulating gene expression. Most CGIs are found at the This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 5′ end of transcripts and behave as functional promoters (13). 1073/pnas.1400604111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1400604111 PNAS | July 1, 2014 | vol. 111 | no. 26 | 9555–9560 Downloaded by guest on October 1, 2021 addition, as a transcriptional activator, HBx modifies diverse HBx13 vs. HBx13). Significant methylation changes were already signal transduction pathways that mediate cellular transformation obvious in the early stage of transformation (Norm3 vs. HBx3) (17, 18). Most HBx transgenic (17) mice spontaneously develop and were maintained during cancer progression (Norm13 vs. HCC at about 1 y of age, providing genetic validation of the HBx13). The methylation levels did not change a lot between oncogenic potential of HBx even in the absence of viral in- different ages compared with the methylation changes caused by tegration and chronic inflammation (6). tumor development. The differentially methylated regions (DMRs) To address the role of HBx viral oncoprotein in the de- were highly enriched in exons, with the most striking changes at velopment of HCC, specifically the aspect of epigenetic regula- CGIs in both age groups (Fig. 1B). To understand the role of DNA tion of the host genome, we examined the differences in DNA methylation changes in the early stage of tumor development, we methylation patterns between normal and HBx-induced liver carried out additional MIRA-seq and RNA-seq analyses of the cancer cells. Intriguingly, DNA methylome analysis revealed 3-mo-old age group to expand the methylation sequence reads dramatic demethylation mainly in the intragenic CGIs with con- up to 170 million for each sample, which covers more than 85% current downregulation of the affected genes. Reanalysis of the of the mouse genome with >70× coverage of the CpG site (SI epigenome data from human cell lines revealed specific epige- Appendix,TableS1B and C). We used these high-density methyl- netic signatures associated with a distinct group of the intragenic omes of 3-mo-old normal and HBx liver to understand the detained CGIs, indicating that they are potential epigenetic regulatory nature of DNA methylation changes caused by HBx. elements for active gene expression. The suppression of Dnmt3L We found 10,553 tumor-associated DMRs (6,668 hyper- and Dnmt3a promoters by HBx appears to cause deficient DNA methylated and 3,885 hypomethylated regions) with differences methyltransferase activity in HBx transgenic (TG) mouse liver, of at least 7 RPKM in the 3-mo-old age group. For comparison, the expected frequency of variations was normalized
Load more

Recommended publications
  • Mouse Germ Line Mutations Due to Retrotransposon Insertions Liane Gagnier1, Victoria P
    Gagnier et al. Mobile DNA (2019) 10:15 https://doi.org/10.1186/s13100-019-0157-4 REVIEW Open Access Mouse germ line mutations due to retrotransposon insertions Liane Gagnier1, Victoria P. Belancio2 and Dixie L. Mager1* Abstract Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrasts with the situation in human, where their relative contribution as germ line insertional mutagens is much lower. In this focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE types involved in these insertional mutations and elaborate on particularly interesting cases. We also discuss differences and similarities between the mutational role of TEs in mice and humans. Keywords: Endogenous retroviruses, Long terminal repeats, Long interspersed elements, Short interspersed elements, Germ line mutation, Inbred mice, Insertional mutagenesis, Transcriptional interference Background promoter and polyadenylation motifs and often a splice The mouse and human genomes harbor similar types of donor site [10, 11]. Sequences of full-length ERVs can TEs that have been discussed in many reviews, to which encode gag, pol and sometimes env, although groups of we refer the reader for more in depth and general infor- LTR retrotransposons with little or no retroviral hom- mation [1–9]. In general, both human and mouse con- ology also exist [6–9]. While not the subject of this re- tain ancient families of DNA transposons, none view, ERV LTRs can often act as cellular enhancers or currently active, which comprise 1–3% of these genomes promoters, creating chimeric transcripts with genes, and as well as many families or groups of retrotransposons, have been implicated in other regulatory functions [11– which have caused all the TE insertional mutations in 13].
    [Show full text]
  • Physical and Functional Interactions Between the Human DNMT3L Protein and Members of the De Novo Methyltransferase Family
    Journal of Cellular Biochemistry 95:902–917 (2005) Physical and Functional Interactions Between the Human DNMT3L Protein and Members of the De Novo Methyltransferase Family Zhao-Xia Chen,1,2 Jeffrey R. Mann,1,2 Chih-Lin Hsieh,3 Arthur D. Riggs,1,2 and Fre´de´ric Che´din1* 1Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010 2Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010 3Departments of Urology and of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California 90033 Abstract The de novo methyltransferase-like protein, DNMT3L, is required for methylation of imprinted genes in germ cells. Although enzymatically inactive, human DNMT3L was shown to act as a general stimulatory factor for de novo methylation by murine Dnmt3a. Several isoforms of DNMT3A and DNMT3B with development-stage and tissue-specific expression patterns have been described in mouse and human, thus bringing into question the identity of the physiological partner(s) for stimulation by DNMT3L. Here, we used an episome-based in vivo methyltransferase assay to systematically analyze five isoforms of human DNMT3A and DNMT3B for activity and stimulation by human DNMT3L. Our results show that human DNMT3A, DNMT3A2, DNMT3B1, and DNMT3B2 are catalytically competent, while DNMT3B3 is inactive in our assay. We also report that the activity of all four active isoforms is significantly increased upon co-expression with DNMT3L, albeit to varying extents. This is the first comprehensive description of the in vivo activities of the poorly characterized human DNMT3A and DNMT3B isoforms and of their functional interactions with DNMT3L.
    [Show full text]
  • DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome
    G C A T T A C G G C A T genes Article DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome Oxana Yu. Naumova 1,2,* , Rebecca Lipschutz 2, Sergey Yu. Rychkov 1, Olga V. Zhukova 1 and Elena L. Grigorenko 2,3,4,* 1 Vavilov Institute of General Genetics RAS, 119991 Moscow, Russia; [email protected] (S.Y.R.); [email protected] (O.V.Z.) 2 Department of Psychology, University of Houston, Houston, TX 77204, USA; [email protected] 3 Department of Psychology, Saint-Petersburg State University, 199034 Saint Petersburg, Russia 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA * Correspondence: [email protected] or [email protected] (O.Y.N.); [email protected] (E.L.G.) Abstract: Recent research has provided evidence on genome-wide alterations in DNA methylation patterns due to trisomy 21, which have been detected in various tissues of individuals with Down syndrome (DS) across different developmental stages. Here, we report new data on the systematic genome-wide DNA methylation perturbations in blood cells of individuals with DS from a previously understudied age group—young children. We show that the study findings are highly consistent with those from the prior literature. In addition, utilizing relevant published data from two other developmental stages, neonatal and adult, we track a quasi-longitudinal trend in the DS-associated DNA methylation patterns as a systematic epigenomic destabilization with age. Citation: Naumova, O.Y.; Lipschutz, R.; Rychkov, S.Y.; Keywords: Down syndrome; infants and toddlers; trisomy 21; DNA methylation; Illumina 450K Zhukova, O.V.; Grigorenko, E.L.
    [Show full text]
  • Structure of Dnmt3a Bound to Dnmt3l Suggests a Model for De Novo DNA Methylation Da Jia, Emory University Renata Z
    Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation Da Jia, Emory University Renata Z. Jurkowska, Jacobs University Bremen Xing Zhang, Emory University Albert Jeltsch, Jacobs University Bremen Xiaodong Cheng, Emory University Journal Title: Nature Volume: Volume 449, Number 7159 Publisher: Nature Publishing Group | 2007-09-13, Pages 248-251 Type of Work: Article | Post-print: After Peer Review Publisher DOI: 10.1038/nature06146 Permanent URL: http://pid.emory.edu/ark:/25593/fj81h Final published version: http://www.nature.com/nature/journal/v449/n7159/full/nature06146.html Copyright information: © 2007 Nature PublishingGroup Accessed September 25, 2021 12:52 AM EDT NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2009 July 20. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nature. 2007 September 13; 449(7159): 248±251. doi:10.1038/nature06146. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation Da Jia1,*, Renata Z. Jurkowska2,*, Xing Zhang1, Albert Jeltsch2, and Xiaodong Cheng1 1Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA 2Biochemistry Laboratory, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany Abstract Genetic imprinting, found in flowering plants and placental mammals, uses DNA methylation to yield gene expression that is dependent on the parent of origin1. DNA methyltransferase 3a (Dnmt3a) and its regulatory factor, DNA methyltransferase 3-like protein (Dnmt3L), are both required for the de novo DNA methylation of imprinted genes in mammalian germ cells.
    [Show full text]
  • Structural Basis for DNMT3A-Mediated De Novo DNA Methylation
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nature. Manuscript Author Author manuscript; Manuscript Author available in PMC 2018 August 07. Published in final edited form as: Nature. 2018 February 15; 554(7692): 387–391. doi:10.1038/nature25477. Structural basis for DNMT3A-mediated de novo DNA methylation Zhi-Min Zhang1,†,*, Rui Lu2,3,*, Pengcheng Wang4, Yang Yu4, Dong-Liang Chen2,3, Linfeng Gao4, Shuo Liu4, Debin Ji5, Scott B Rothbart3,6, Yinsheng Wang4,5, Gang Greg Wang2,3,§, and Jikui Song1,4,§ 1Department of Biochemistry, University of California, Riverside, USA 2The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, USA 3Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, USA 4Environmental Toxicology Graduate Program and 5Department of Chemistry, University of California, Riverside, USA 6Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan, USA Abstract DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is essential for genome regulation and development1, 2. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A–DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells.
    [Show full text]
  • Dnmt3l Antibody
    Efficient Professional Protein and Antibody Platforms Dnmt3L Antibody Basic information: Catalog No.: UMA60671 Source: Mouse Size: 50ul/100ul Clonality: Monoclonal Concentration: 1mg/ml Isotype: Mouse IgG1 Purification: Protein G affinity purified Useful Information: ICC:1:200-1:500 Applications: IHC:1:200 Reactivity: -- Specificity: This antibody recognizes Dnmt3L protein. Immunogen: recombinant protein DNA (cytosine-5)-methyltransferase 3-like is an enzyme that in humans is encoded by the DNMT3L gene. CpG methylation is an epigenetic modifica- tion that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a nuclear protein with similarity to DNA methyltransferases. This protein is Description: not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, this protein does stimulate de novo methylation by DNA cytosine methyl- transferase 3 alpha and it is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional re- pression through interaction with histone deacetylase 1. Uniprot: Q9UJW3 BiowMW: 44kDa Buffer: 1*TBS (pH7.4), 1%BSA, 40%Glycerol. Preservative: 0.05% Sodium Azide. Storage: Store at 4°C short term and -20°C long term. Avoid freeze-thaw cycles. Note: For research use only, not for use in diagnostic procedure. Data: ICC staining DNMT3L in HepG2 cells (red). Cells were fixed in paraformaldehyde, permeabilised with 0.25% Triton X100/PBS and counterstained with DAPI in order to highlight the nucleus (blue). Gene Universal Technology Co. Ltd www.universalbiol.com Tel: 0550-3121009 E-mail: [email protected] Efficient Professional Protein and Antibody Platforms ICC staining DNMT3L in NCCIT cells (red).
    [Show full text]
  • Structural Basis for Impairment of DNA Methylation by the DNMT3A R882H Mutation ✉ Hiwot Anteneh1, Jian Fang1 & Jikui Song 1
    ARTICLE https://doi.org/10.1038/s41467-020-16213-9 OPEN Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation ✉ Hiwot Anteneh1, Jian Fang1 & Jikui Song 1 DNA methyltransferase DNMT3A is essential for establishment of mammalian DNA methylation during development. The R882H DNMT3A is a hotspot mutation in acute myeloid leukemia (AML) causing aberrant DNA methylation. However, how this mutation 1234567890():,; affects the structure and function of DNMT3A remains unclear. Here we report structural characterization of wild-type and R882H-mutated DNMT3A in complex with DNA substrates with different sequence contexts. A loop from the target recognition domain (TRD loop) recognizes the CpG dinucleotides in a +1 flanking site-dependent manner. The R882H mutation reduces the DNA binding at the homodimeric interface, as well as the molecular link between the homodimeric interface and TRD loop, leading to enhanced dynamics of TRD loop. Consistently, in vitro methylation analyses indicate that the R882H mutation com- promises the enzymatic activity, CpG specificity and flanking sequence preference of DNMT3A. Together, this study uncovers multiple defects of DNMT3A caused by the R882H mutation in AML. ✉ 1 Department of Biochemistry, University of California, Riverside, CA 92521, USA. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:2294 | https://doi.org/10.1038/s41467-020-16213-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16213-9 NA methylation is an important epigenetic mechanism loop, leading to altered conformational flexibility of the TRD loop that critically impacts cell proliferation and lineage and its context-dependent DNA contact.
    [Show full text]
  • Dnmt3l Antagonizes DNA Methylation at Bivalent Promoters and Favors DNA Methylation at Gene Bodies in Escs
    Dnmt3L Antagonizes DNA Methylation at Bivalent Promoters and Favors DNA Methylation at Gene Bodies in ESCs Francesco Neri,1,4 Anna Krepelova,1,2,4 Danny Incarnato,1,2 Mara Maldotti,1 Caterina Parlato,1 Federico Galvagni,2 Filomena Matarese,3 Hendrik G. Stunnenberg,3 and Salvatore Oliviero1,2,* 1Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy 2Dipartimento di Biotecnologie, Chimica e Farmacia, Universita` degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy 3Nijmegen Center for Molecular Life Sciences, Department of Molecular Biology, 6500 HB Nijmegen, The Netherlands 4These authors contributed equally to this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2013.08.056 SUMMARY DNA methylation is mediated by DNA methyltransferases (Dnmt), which include the maintenance enzyme Dnmt1 and the The de novo DNA methyltransferase 3-like (Dnmt3L) de novo Dnmt3. The family of the Dnmt3 includes two catalyti- is a catalytically inactive DNA methyltransferase cally active members, Dnmt3a and Dnmt3b, and a catalytically that cooperates with Dnmt3a and Dnmt3b to meth- inactive member called Dnmt3-like (Dnmt3L) (Bestor, 2000)(Ju- ylate DNA. Dnmt3L is highly expressed in mouse rkowska et al., 2011b). embryonic stem cells (ESCs), but its function in these A crystallography study showed that Dnmt3L forms a hetero- cells is unknown. Through genome-wide analysis of tetrameric complex with Dnmt3a (Jia et al., 2007). It has been suggested that this tetramerization prevents Dnmt3a oligomeri- Dnmt3L knockdown in ESCs, we found that Dnmt3L zation and localization in heterochromatin (Jurkowska et al., is a positive regulator of methylation at the gene 2011a).
    [Show full text]
  • (DNMT) Family and Ten-Eleven-Translocation (TET) Enzymes Family in Pan-Cancer
    Comprehensive Analysis of DNA Methylation Regulator DNA Methyltransferase (DNMT) Family and Ten-Eleven-Translocation (TET) Enzymes Family in Pan-Cancer Cheng Ouyang The First Aliated Hospital of China Medical University Hao Li The First Aliated Hospital of China Medical University Liping Sun ( [email protected] ) The First Aliated Hospital of China Medical University https://orcid.org/0000-0003-3637-0305 Research Keywords: DNA methylation, DNMT, TET enzymes, pan-cancer, prognosis Posted Date: January 29th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-154338/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/26 Abstract Background: DNA methyltransferase (DNMT) family and ten-eleven-translocation (TET) family enzymes play pivotal roles in regulating DNA methylation, and are closely related to diverse cancers. This study was designed to clarify the specic roles of DNMT and TET genes in pan-cancers. Methods: The expression, mutation, copy number variations (CNVs), cancer-related pathways, immune cell inltration correlation, and prognostic potential of DNMT/TET genes were systematically investigated in 33 cancer types using next-generation sequence data from the Cancer Genome Atlas database. Results: DNMT3B was more highly expressed in the majority of tumors analyzed than in normal tissues. Most DNMT/TET genes were frequently mutated in uterine carcinosarcoma, and TET1 and TET2 showed higher mutation frequencies in various cancer types. DNMT3B exhibited inclusive copy number amplication in almost all cancers, such as stomach adenocarcinoma(STAD) and colon adenocarcinoma(COAD)l, while most DNMT/TET genes displayed highly copy number deletion in kidney chromophobeKICH.
    [Show full text]
  • HDAC1 and HDAC2 in Mouse Oocytes and Preimplantation Embryos: Specificity Versus Compensation
    Cell Death and Differentiation (2016) 23, 1119–1127 & 2016 Macmillan Publishers Limited All rights reserved 1350-9047/16 www.nature.com/cdd Review HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation P Ma*,1 and RM Schultz1 Oocyte and preimplantation embryo development entail dynamic changes in chromatin structure and gene expression, which are regulated by a number of maternal and zygotic epigenetic factors. Histone deacetylases (HDACs), which tighten chromatin structure, repress transcription and gene expression by removing acetyl groups from histone or non-histone proteins. HDAC1 and HDAC2 are two highly homologous Class I HDACs and display compensatory or specific roles in different cell types or in response to different stimuli and signaling pathways. We summarize here the current knowledge about the functions of HDAC1 and HDAC2 in regulating histone modifications, transcription, DNA methylation, chromosome segregation, and cell cycle during oocyte and preimplantation embryo development. What emerges from these studies is that although HDAC1 and HDAC2 are highly homologous, HDAC2 is more critical than HDAC1 for oocyte development and reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development. Cell Death and Differentiation (2016) 23, 1119–1127; doi:10.1038/cdd.2016.31; published online 15 April 2016 Facts HDAC1/2-containing complexes in defining steady-state levels of acetylated histones? • HDAC1 and HDAC2 show different expression profiles • What non-histone proteins are deacetylated by HDAC1 and/ during oocyte and preimplantation development. or HDAC2 in oocytes and preimplantation embryos, and what • HDAC1 and HDAC2 regulate oocyte development through are the functional consequences of their deacetylation? transcription in a dosage-dependent manner.
    [Show full text]
  • Meiotic and Epigenetic Defects in Dnmt3l-Knockout Mouse Spermatogenesis
    Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis Kylie E. Webster*†, Moira K. O’Bryan†‡, Stephen Fletcher§, Pauline E. Crewther*, Ulla Aapola¶, Jeff Craigʈ, Dion K. Harrison§, Hnin Aung§, Nawapen Phutikanit§, Robert Lyle**, Sarah J. Meachem††, Stylianos E. Antonarakis**, David M. de Kretser‡, Mark P. Hedger‡,Pa¨ rt Peterson‡‡, Bernard J. Carroll§,§§, and Hamish S. Scott*¶¶ *Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; ‡Centre for Molecular Reproduction and Endocrinology, Monash Institute of Reproduction and Development, Australian Research Council Centre of Excellencein Biotechnology and Development, Monash University, Clayton, Victoria 3168, Australia; §Schools of Molecular and Microbial Sciences and Land and Food Sciences and §§Australian Research Council Centre of Excellence for Integrative Legume Research and Institute of Molecular Bioscience, University of Queensland, Brisbane 4072, Australia; ¶Institute of Medical Technology and Department of Pathology, Biokatu 6, Tampere University Hospital, 33014 University of Tampere, Fin-33521, Tampere, Finland; ʈChromosome Research Group, The Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia; **Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, CMU, 1, Rue Michel Servet, 1211 Geneva, Switzerland; ††Prince Henry’s Institute of Medical
    [Show full text]
  • The N-Terminus of Histone H3 Is Required for De Novo DNA Methylation in Chromatin
    The N-terminus of histone H3 is required for de novo DNA methylation in chromatin Jia-Lei Hua,b, Bo O. Zhoua,b, Run-Rui Zhanga,b, Kang-Ling Zhangc, Jin-Qiu Zhoua,1, and Guo-Liang Xua,1 aThe State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; bThe Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; and cDepartment of Biochemistry, School of Medicine, Loma Linda University, Loma Linda, CA 92350 Edited by Arthur D. Riggs, Beckman Research Institute of the City of Hope, Duarte, CA, and approved November 3, 2009 (received for review May 28, 2009) DNA methylation and histone modification are two major epige- maintenance methylation. For example, recent studies showed netic pathways that interplay to regulate transcriptional activity that G9a exerts its effect on DNA methylation independently of and other genome functions. Dnmt3L is a regulatory factor for the its enzymatic activity (6–8), and depletion of this protein might de novo DNA methyltransferases Dnmt3a and Dnmt3b. Although have an impact on the maintenance function of Dnmt1 (9, 10). recent biochemical studies have revealed that Dnmt3L binds to the While a repressive mark such as H3K9 methylation can tail of histone H3 with unmethylated lysine 4 in vitro, the require- presumably trigger DNA methylation, the active chromatin mark ment of chromatin components for DNA methylation has not been H3K4 methylation has been implicated as a repulsive signal (11). examined, and functional evidence for the connection of histone Dnmt3L, the regulatory protein that forms a complex with tails to DNA methylation is still lacking.
    [Show full text]