DNA methylation dynamics in health and disease

DNA methylation is an epigenetic mark that is erased in the early embryo and then re-established at the time of implantation. In this Review, dynamics of DNA methylation during normal development in vivo are discussed, starting from fertilization through embryogenesis and postnatal growth, as well as abnormal methylation changes that occur in cancer.

[1]  M. Szyf,et al.  Replacement of 5-methylcytosine by cytosine: a possible mechanism for transient DNA demethylation during differentiation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Torchia,et al.  TGF-β-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex. , 2012, Molecular cell.

[3]  N. Sonenberg,et al.  UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells , 2007, Science.

[4]  J. D. Engel,et al.  Fine Tuning of Globin Gene Expression by DNA Methylation , 2006, PloS one.

[5]  Robert S. Illingworth,et al.  CpG islands influence chromatin structure via the CpG-binding protein Cfp1 , 2010, Nature.

[6]  Wolfgang Huber,et al.  A high-resolution map of transcription in the yeast genome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[7]  E. Canaani,et al.  TrxG and PcG Proteins but Not Methylated Histones Remain Associated with DNA through Replication , 2012, Cell.

[8]  Z. Deng,et al.  The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes , 2011, Nature.

[9]  A. Hattersley,et al.  Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57 , 2008, Nature Genetics.

[10]  J. Locker,et al.  Developmental changes in the methylation of the rat albumin and alpha‐fetoprotein genes. , 1983, The EMBO journal.

[11]  X. Li,et al.  A Histone Acetyltransferase Regulates Active DNA Demethylation in Arabidopsis , 2012, Science.

[12]  M. Shirakawa,et al.  Structural basis for recognition of H 3 K 4 methylation status by the DNA methyltransferase 3 A ATRX – DNMT 3 – DNMT 3 L domain , 2013 .

[13]  J. Stroud,et al.  Multiple elements influence transcriptional regulation from the human testis-specific PGK2 promoter in transgenic mice. , 1999, Biology of reproduction.

[14]  Howard Cedar,et al.  DNA methylation represses transcription in vivo , 1999, Nature Genetics.

[15]  H. Cedar,et al.  Developmental regulation of immune system gene rearrangement. , 1999, Current opinion in immunology.

[16]  S. Baylin,et al.  Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. , 2011, Cancer cell.

[17]  Z. Siegfried,et al.  DNA methylation: A molecular lock , 1997, Current Biology.

[18]  W. Reik,et al.  5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. , 2011, Nature communications.

[19]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[20]  J. Herman,et al.  Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. , 2003, Cancer research.

[21]  Adrian Bird,et al.  Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. , 2012, Genes & development.

[22]  V. Chapman,et al.  Differences in DNA methylation during oogenesis and spermatogenesis and their persistence during early embryogenesis in the mouse. , 1987, Genes & development.

[23]  Colin C. Collins,et al.  Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors , 2002, Nature Genetics.

[24]  Cassandra R. Farthing,et al.  Global Mapping of DNA Methylation in Mouse Promoters Reveals Epigenetic Reprogramming of Pluripotency Genes , 2008, PLoS genetics.

[25]  W. Reik,et al.  Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5 , 2008, Nature Cell Biology.

[26]  Yi Zhang,et al.  Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. , 2011, Genes & development.

[27]  H. Cedar,et al.  Linking DNA methylation and histone modification: patterns and paradigms , 2009, Nature Reviews Genetics.

[28]  G. Ming,et al.  Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain , 2011, Cell.

[29]  Israel Steinfeld,et al.  Developmental programming of CpG island methylation profiles in the human genome , 2009, Nature Structural &Molecular Biology.

[30]  C. Allis,et al.  DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA , 2007, Nature.

[31]  L. Sowers,et al.  Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. , 2007, Cancer research.

[32]  L. Sowers,et al.  An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  W. Reik,et al.  Active demethylation of the paternal genome in the mouse zygote , 2000, Current Biology.

[34]  A. Razin,et al.  Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line. , 1992, Genes & development.

[35]  D. Riesner,et al.  Induction of Tumors in Mice by Genomic Hypomethylation , 2003 .

[36]  Y. Bergman,et al.  A Unique Developmental Pattern of Oct-3/4DNA Methylation Is Controlled by a cis-demodification Element* , 2002, The Journal of Biological Chemistry.

[37]  Alun D. Hughes,et al.  The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression , 2008, Oncogene.

[38]  G. Pfeifer,et al.  Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine , 2011, Proceedings of the National Academy of Sciences.

[39]  J. Walter,et al.  Embryogenesis: Demethylation of the zygotic paternal genome , 2000, Nature.

[40]  A. Bird,et al.  Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. , 1994, Genes & development.

[41]  Wolfgang Wagner,et al.  Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. , 2010, Genome research.

[42]  S. Jacobsen,et al.  UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells , 2007, Science.

[43]  Nita Ahuja,et al.  Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. , 2012, Cancer cell.

[44]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in X Inactivation , 2003, Science.

[45]  Robert S. Illingworth,et al.  Cfp 1 integrates both CpG content and gene activity for accurate H 3 K 4 me 3 deposition in embryonic stem cells , 2012 .

[46]  G. Reifenberger,et al.  IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics , 2012, Nature.

[47]  H. Cedar,et al.  B cell-specific demethylation: A novel role for the intronic κ chain enhancer sequence , 1994, Cell.

[48]  J. Jost,et al.  Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[49]  F. Papavasiliou,et al.  Cytidine deaminases: AIDing DNA demethylation? , 2010, Genes & development.

[50]  DNA Demethylation In Vitro Involvement of RNA , 1998, Cell.

[51]  Brian J. Stevenson,et al.  Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. , 2012, Genome research.

[52]  A. Razin,et al.  Substrate and sequence specificity of a eukaryotic DNA methylase , 1982, Nature.

[53]  J. Jost,et al.  An estrogen-dependent demethylation at the 5' end of the chicken vitellogenin gene is independent of DNA synthesis. , 1984, Nucleic acids research.

[54]  M. Szyf,et al.  Gene Methylation Patterns and Expression , 1984 .

[55]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[56]  Paul Tempst,et al.  MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex , 1999, Nature Genetics.

[57]  Gangning Liang,et al.  DNA methylation screening identifies driver epigenetic events of cancer cell survival. , 2012, Cancer cell.

[58]  K. Mitsuya,et al.  The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA , 2007, Nature.

[59]  H. Cedar,et al.  Role of DNA Methylation in Stable Gene Repression* , 2007, Journal of Biological Chemistry.

[60]  T. Bestor,et al.  Dnmt3L and the Establishment of Maternal Genomic Imprints , 2001, Science.

[61]  Owen T McCann,et al.  Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. , 2010, Genome research.

[62]  Satoshi Tanaka,et al.  PGC7/Stella protects against DNA demethylation in early embryogenesis , 2007, Nature Cell Biology.

[63]  A. Razin,et al.  Methylation of foreign DNA sequences in eukaryotic cells. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[64]  M. Lyon,et al.  Age related reactivation of an X-linked gene , 1987, Nature.

[65]  P. Laird,et al.  Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina–associated domains , 2011, Nature Genetics.

[66]  Kelly M. McGarvey,et al.  A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing , 2007, Nature Genetics.

[67]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[68]  M. Szyf,et al.  A mammalian protein with specific demethylase activity for mCpG DNA , 1999, Nature.

[69]  Yang Wang,et al.  Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA , 2011, Science.

[70]  P. Fahey,et al.  Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model , 2010, PLoS genetics.

[71]  B. Turner,et al.  Histone acetylation and X inactivation. , 1998, Developmental genetics.

[72]  B. Migeon,et al.  DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[73]  A. Razin,et al.  Methylation changes in the apolipoprotein AI gene during embryonic development of the mouse. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Y. Shinkai,et al.  PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos , 2012, Nature.

[75]  H. Leonhardt,et al.  A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei , 1992, Cell.

[76]  F. Lienert,et al.  Identification of genetic elements that autonomously determine DNA methylation states , 2011, Nature Genetics.

[77]  N. Benvenisty,et al.  Sequential changes in DNA methylation patterns of the rat phosphoenolpyruvate carboxykinase gene during development. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[78]  Zachary D. Smith,et al.  A unique regulatory phase of DNA methylation in the early mammalian embryo , 2012, Nature.

[79]  Z. Siegfried,et al.  Spl elements protect a CpG island from de novo methylation , 1994, Nature.

[80]  Howard Cedar,et al.  Programming of DNA methylation patterns. , 2012, Annual review of biochemistry.

[81]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[82]  Riitta Lahesmaa,et al.  Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. , 2011, Cell stem cell.

[83]  Z. Paroush,et al.  Dynamics of demethylation and activation of the α-actin gene in myoblasts , 1990, Cell.

[84]  J. Hurst,et al.  DNA methylation and the regulation of globin gene expression , 1983, Cell.

[85]  S. Lehnert,et al.  Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. , 1987, Development.

[86]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[87]  Xiaodong Cheng,et al.  Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation , 2012, Nucleic acids research.

[88]  Zohar Yakhini,et al.  Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer , 2007, Nature Genetics.

[89]  H. Koseki,et al.  Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors. , 2011, Progress in molecular biology and translational science.

[90]  Martin Renqiang Min,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[91]  M. Shirakawa,et al.  Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX–DNMT3–DNMT3L domain , 2009, EMBO reports.

[92]  N. Brockdorff,et al.  Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. , 2003, Developmental cell.

[93]  Huijue Jia,et al.  AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation , 2012, Nature chemical biology.

[94]  U. Storb,et al.  Hypomethylation is necessary but not sufficient for V(D)J recombination within a transgenic substrate. , 1999, Molecular Immunology.

[95]  E. Whitelaw,et al.  Transgenerational epigenetic inheritance: more questions than answers. , 2010, Genome research.

[96]  Y. Bergman,et al.  Extinction of Oct-3/4 gene expression in embryonal carcinoma x fibroblast somatic cell hybrids is accompanied by changes in the methylation status, chromatin structure, and transcriptional activity of the Oct-3/4 upstream region , 1993, Molecular and cellular biology.

[97]  H. Cedar,et al.  De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes , 2008, Nature Structural &Molecular Biology.

[98]  Nianxiang Zhang,et al.  Widespread and Tissue Specific Age-related Dna Methylation Material Supplemental Related Content a Hallmark of Cancer Age-dependent Dna Methylation of Genes That Are Suppressed in Stem Cells Is , 2022 .

[99]  Stephanie Daignault,et al.  Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer. , 2006, Cancer research.

[100]  R. Jaenisch,et al.  Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[101]  P. Leder,et al.  A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. , 2008, Developmental cell.

[102]  Lanlan Shen,et al.  Characteristic methylation profile in CpG island methylator phenotype‐negative distal colorectal cancers , 2010, International journal of cancer.

[103]  Michael B. Stadler,et al.  Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome , 2007, Nature Genetics.

[104]  Kairong Cui,et al.  Dual functions of Tet 1 in transcriptional regulation in mouse embryonic stem cells , 2011 .

[105]  Peter A. Jones,et al.  Rethinking how DNA methylation patterns are maintained , 2009, Nature Reviews Genetics.

[106]  A. Feinberg,et al.  Hypomethylation distinguishes genes of some human cancers from their normal counterparts , 1983, Nature.

[107]  Keji Zhao,et al.  Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells , 2011, Nature.

[108]  M. Pellegrini,et al.  Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency , 2010, Nature.

[109]  A. Razin,et al.  The ontogeny of allele‐specific methylation associated with imprinted genes in the mouse. , 1993, The EMBO journal.

[110]  P. Jones,et al.  Inhibition of DNA methylation by 5-aza-2'-deoxycytidine suppresses the growth of human tumor cell lines. , 1998, Cancer research.

[111]  Chia-Lin Wei,et al.  Dynamic changes in the human methylome during differentiation. , 2010, Genome research.

[112]  Gangning Liang,et al.  Cooperativity between DNA Methyltransferases in the Maintenance Methylation of Repetitive Elements , 2002, Molecular and Cellular Biology.

[113]  Howard Cedar,et al.  A role for nuclear NF–κB in B–cell–specific demethylation of the Igκ locus , 1996, Nature Genetics.

[114]  Gangning Liang,et al.  Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line , 2008, Proceedings of the National Academy of Sciences.

[115]  G. Martin,et al.  Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation , 1987, Cell.

[116]  T. Mikkelsen,et al.  Genome-scale DNA methylation maps of pluripotent and differentiated cells , 2008, Nature.

[117]  Jim Stalker,et al.  A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci , 2008, PLoS biology.

[118]  P. Laird,et al.  Epigenetic stem cell signature in cancer , 2007, Nature Genetics.

[119]  R. Weinberg,et al.  Suppression of intestinal neoplasia by DNA hypomethylation , 1995, Cell.

[120]  H. Cedar,et al.  G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis , 2006, Nature Cell Biology.

[121]  I. Simon,et al.  Evidence for an instructive mechanism of de novo methylation in cancer cells , 2006, Nature Genetics.

[122]  Yi Zhang,et al.  Replication-Dependent Loss of 5-Hydroxymethylcytosine in Mouse Preimplantation Embryos , 2011, Science.

[123]  G. Montana,et al.  Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome , 2012, Developmental cell.

[124]  D. Bruusgaard [Cause of or consequence of?]. , 2011, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[125]  R. Grainger,et al.  Delta-crystallin genes become hypomethylated in postmitotic lens cells during chicken development. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[126]  H. Tapp,et al.  Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa. , 2010, Carcinogenesis.

[127]  Steffen Jung,et al.  Epigenetic ontogeny of the Igk locus during B cell development , 2005, Nature Immunology.

[128]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[129]  A. Riggs,et al.  DNA methylation, biochemistry, and biological significance , 1984 .

[130]  Peter A. Jones,et al.  Cancer genetics and epigenetics: two sides of the same coin? , 2012, Cancer cell.

[131]  Min Chen,et al.  DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer , 2011, Molecular Cancer Therapeutics.

[132]  H. Cedar,et al.  Muscle-specific activation of a methylated chimeric actin gene , 1986, Cell.

[133]  S. Baylin,et al.  Altered methylation patterns in cancer cell genomes: cause or consequence? , 2002, Cancer cell.