DNA methylation: superior or subordinate in the epigenetic hierarchy?

Epigenetic modifications are heritable changes in gene expression not encoded by the DNA sequence. In the past decade, great strides have been made in characterizing epigenetic changes during normal development and in disease states like cancer. However, the epigenetic landscape has grown increasingly complicated, encompassing DNA methylation, the histone code, noncoding RNA, and nucleosome positioning, along with DNA sequence. As a stable repressive mark, DNA methylation, catalyzed by the DNA methyltransferases (DNMTs), is regarded as a key player in epigenetic silencing of transcription. DNA methylation may coordinately regulate the chromatin status via the interaction of DNMTs with other modifications and with components of the machinery mediating those marks. In this review, we will comprehensively examine the current understanding of the connections between DNA methylation and other epigenetic marks and discuss molecular mechanisms of transcriptional repression in development and in carcinogenesis.

[1]  S. Baylin,et al.  Stem Cell Chromatin Patterns: An Instructive Mechanism for DNA Hypermethylation? , 2007, Cell cycle.

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

[3]  Peter A. Jones,et al.  Epigenetics in human disease and prospects for epigenetic therapy , 2004, Nature.

[4]  P. Jones,et al.  The DNA methylation paradox. , 1999, Trends in genetics : TIG.

[5]  M. Pellegrini,et al.  Relationship between nucleosome positioning and DNA methylation , 2010, Nature.

[6]  P. Wade.  Methyl CpG‐binding proteins and transcriptional repression * , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[7]  Kohta Ikegami,et al.  Genome‐wide and locus‐specific DNA hypomethylation in G9a deficient mouse embryonic stem cells , 2007, Genes to cells : devoted to molecular & cellular mechanisms.

[8]  Madeleine P. Ball,et al.  Corrigendum: Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells , 2009, Nature Biotechnology.

[9]  S. Henikoff,et al.  DNA demethylation by DNA repair. , 2009, Trends in genetics : TIG.

[10]  F. Kisseljov,et al.  DNA Demethylation and Carcinogenesis , 2005, Biochemistry (Moscow).

[11]  Shireen A. Sarraf,et al.  Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. , 2004, Molecular cell.

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

[13]  S. Jacobsen,et al.  Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells , 2009, Proceedings of the National Academy of Sciences.

[14]  H. Shibuya,et al.  DNA demethylation in hormone-induced transcriptional derepression , 2009, Nature.

[15]  A. Probst,et al.  Epigenetic inheritance during the cell cycle , 2009, Nature Reviews Molecular Cell Biology.

[16]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5- Hydroxymethylcytosine in Mammalian DNA by the MLL Partner TET1 , 2009 .

[17]  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.

[18]  Helen M. Blau,et al.  Reprogramming towards pluripotency requires AID-dependent DNA demethylation , 2010, Nature.

[19]  Martin S. Taylor,et al.  Genome-wide analysis of mammalian promoter architecture and evolution , 2006, Nature Genetics.

[20]  K. Robertson,et al.  DNMT1 and DNMT3B modulate distinct polycomb-mediated histone modifications in colon cancer. , 2009, Cancer research.

[21]  S. Dhanasekaran,et al.  The polycomb group protein EZH2 is involved in progression of prostate cancer , 2002, Nature.

[22]  En Li,et al.  Suv 39 h-Mediated Histone H 3 Lysine 9 Methylation Directs DNA Methylation to Major Satellite Repeats at Pericentric Heterochromatin , 2003 .

[23]  D. Reinberg,et al.  Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. , 2002, Genes & development.

[24]  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.

[25]  J. A. Wamstad,et al.  Polycomb Group and SCF Ubiquitin Ligases Are Found in a Novel BCOR Complex That Is Recruited to BCL6 Targets , 2006, Molecular and Cellular Biology.

[26]  T. Bestor,et al.  The DNA methyltransferases of mammals. , 2000, Human molecular genetics.

[27]  J. Herman,et al.  Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. , 2003, Cancer cell.

[28]  Qian Tao,et al.  DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. , 2008, Human molecular genetics.

[29]  O. Gangisetty,et al.  Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. , 2006, Genes & development.

[30]  E. Li.  Chromatin modification and epigenetic reprogramming in mammalian development , 2002, Nature Reviews Genetics.

[31]  Peter A. Jones,et al.  Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival , 2006, Proceedings of the National Academy of Sciences.

[32]  Jian‐Kang Zhu.  Active DNA demethylation mediated by DNA glycosylases. , 2009, Annual review of genetics.

[33]  K. Robertson,et al.  DNA methylation in development and human disease. , 2008, Mutation research.

[34]  A. Feinberg,et al.  The epigenetic progenitor origin of human cancer , 2006, Nature Reviews Genetics.

[35]  J. Qin,et al.  ICBP90, a Novel Methyl K9 H3 Binding Protein Linking Protein Ubiquitination with Heterochromatin Formation , 2007, Molecular and Cellular Biology.

[36]  Yi Zhang,et al.  The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. , 2004, Current opinion in genetics & development.

[37]  D. Zilberman,et al.  Genome-Wide Evolutionary Analysis of Eukaryotic DNA Methylation , 2010, Science.

[38]  Thomas A Milne,et al.  MLL targets SET domain methyltransferase activity to Hox gene promoters. , 2002, Molecular cell.

[39]  S. Pradhan,et al.  Functional cooperation between HP1 and DNMT1 mediates gene silencing. , 2007, Genes & development.

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

[41]  Tom Misteli,et al.  Maintenance of Stable Heterochromatin Domains by Dynamic HP1 Binding , 2003, Science.

[42]  C. Allis,et al.  Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. , 2007, Molecular cell.

[43]  A. Riggs,et al.  Methylation and epigenetic fidelity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Yoichi Shinkai,et al.  SET Domain-containing Protein, G9a, Is a Novel Lysine-preferring Mammalian Histone Methyltransferase with Hyperactivity and Specific Selectivity to Lysines 9 and 27 of Histone H3* , 2001, The Journal of Biological Chemistry.

[45]  Yusuke Nakamura,et al.  Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism , 2008, Nature.

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

[47]  G. Teebor,et al.  5-Hydroxymethylcytosine DNA glycosylase activity in mammalian tissue. , 1988, Biochemical and biophysical research communications.

[48]  V. Ingram,et al.  Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. , 1988, Journal of molecular biology.

[49]  Peter A. Jones,et al.  Selective Anchoring of DNA Methyltransferases 3A and 3B to Nucleosomes Containing Methylated DNA , 2009, Molecular and Cellular Biology.

[50]  A. Stein,et al.  Histone H1 Depletion in Mammals Alters Global Chromatin Structure but Causes Specific Changes in Gene Regulation , 2005, Cell.

[51]  S. Henikoff,et al.  Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks , 2008, Nature.

[52]  T. Kouzarides,et al.  The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. , 2003, Nucleic acids research.

[53]  Albert Jeltsch,et al.  The Dnmt3a PWWP Domain Reads Histone 3 Lysine 36 Trimethylation and Guides DNA Methylation* , 2010, The Journal of Biological Chemistry.

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

[55]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[56]  Steven Henikoff,et al.  Phylogenomics of the nucleosome , 2003, Nature Structural Biology.

[57]  R. Paro,et al.  Polycomb/Trithorax response elements and epigenetic memory of cell identity , 2007, Development.

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

[59]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[60]  Wim Van Criekinge,et al.  Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells. , 2008, Cancer research.

[61]  A. Riggs,et al.  A human B cell methylome at 100−base pair resolution , 2009, Proceedings of the National Academy of Sciences.

[62]  M. Siegmann,et al.  5-Methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. , 2000, Nucleic acids research.

[63]  Reuben S Harris,et al.  Immunity through DNA deamination. , 2003, Trends in biochemical sciences.

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

[65]  G. Ast,et al.  Chromatin organization marks exon-intron structure , 2009, Nature Structural &Molecular Biology.

[66]  Wendy Dean,et al.  Activation-induced Cytidine Deaminase Deaminates 5-Methylcytosine in DNA and Is Expressed in Pluripotent Tissues , 2004, Journal of Biological Chemistry.

[67]  Michael B. Stadler,et al.  Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. , 2008, Molecular cell.

[68]  M. Clarke,et al.  Stem Cells and Cancer: Two Faces of Eve , 2006, Cell.

[69]  S. Schreiber,et al.  Histone Variant H2A.Z Marks the 5′ Ends of Both Active and Inactive Genes in Euchromatin , 2006, Cell.

[70]  Brigitte Wild,et al.  Histone Methyltransferase Activity of a Drosophila Polycomb Group Repressor Complex , 2002, Cell.

[71]  B. Cairns,et al.  DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45 , 2008, Cell.

[72]  J. Widom,et al.  Role of DNA sequence in nucleosome stability and dynamics , 2001, Quarterly Reviews of Biophysics.

[73]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[74]  Hélène Rogniaux,et al.  Disruption of Dnmt1/PCNA/UHRF1 Interactions Promotes Tumorigenesis from Human and Mice Glial Cells , 2010, PloS one.

[75]  F. Chédin,et al.  Reconstitution and Mechanism of the Stimulation of de Novo Methylation by Human DNMT3L* , 2006, Journal of Biological Chemistry.

[76]  Mark Groudine,et al.  Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells , 2004, Nature Structural &Molecular Biology.

[77]  R. Blumenthal,et al.  Mammalian DNA methyltransferases: a structural perspective. , 2008, Structure.

[78]  Bronwen L. Aken,et al.  Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences , 2007, Nature.

[79]  D. Zilberman,et al.  Genome-Wide Demethylation of Arabidopsis Endosperm , 2009, Science.

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

[81]  Robert L Moritz,et al.  PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing , 2009, Nature Structural &Molecular Biology.

[82]  J. Jiricny,et al.  DNA Cytosine Demethylation: Are We Getting Close? , 2008, Cell.

[83]  S. Méresse,et al.  Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[84]  Tomohiro Hayakawa,et al.  Maintenance of self‐renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b , 2006, Genes to cells : devoted to molecular & cellular mechanisms.

[85]  I. Suetake,et al.  Distinct DNA methylation activity of Dnmt3a and Dnmt3b towards naked and nucleosomal DNA. , 2006, Journal of biochemistry.

[86]  E. Li,et al.  The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation , 2009, Nature Genetics.

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

[88]  H. Kato,et al.  G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. , 2002, Genes & development.

[89]  T. Bestor,et al.  A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. , 1998, Human molecular genetics.

[90]  A. Feinberg,et al.  Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells , 2009, Nature Genetics.

[91]  H. Kimura,et al.  G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription , 2008, The EMBO journal.

[92]  G. Almouzni,et al.  HP1 and the dynamics of heterochromatin maintenance , 2004, Nature Reviews Molecular Cell Biology.

[93]  Raja Jothi,et al.  Genome-Wide uH2A Localization Analysis Highlights Bmi1-Dependent Deposition of the Mark at Repressed Genes , 2009, PLoS genetics.

[94]  Xiaoyu Zhang,et al.  Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2 , 2006, Science.

[95]  C. Allis,et al.  Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers , 2010, Nature Reviews Cancer.

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

[97]  E. Segal,et al.  What controls nucleosome positions? , 2009, Trends in genetics : TIG.

[98]  J. Zlatanova,et al.  The Middle Region of an HP1-binding Protein, HP1-BP74, Associates with Linker DNA at the Entry/Exit Site of Nucleosomal DNA* , 2009, The Journal of Biological Chemistry.

[99]  E. Li,et al.  Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases , 1998, Nature Genetics.

[100]  K. Robertson.  DNA methylation and human disease , 2005, Nature Reviews Genetics.

[101]  Kohta Ikegami,et al.  Interplay between DNA methylation, histone modification and chromatin remodeling in stem cells and during development. , 2009, The International journal of developmental biology.

[102]  V. Pirrotta,et al.  Drosophila Enhancer of Zeste/ESC Complexes Have a Histone H3 Methyltransferase Activity that Marks Chromosomal Polycomb Sites , 2002, Cell.

[103]  Yi Zhang,et al.  Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. , 2005, Molecular cell.

[104]  N. Heintz,et al.  The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain , 2009, Science.

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

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

[107]  Allen D. Delaney,et al.  Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters , 2010, Nature.

[108]  Cizhong Jiang,et al.  Nucleosome positioning and gene regulation: advances through genomics , 2009, Nature Reviews Genetics.

[109]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[110]  S. Lau,et al.  5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation , 2007, Oncogene.

[111]  Jeong-Heon Lee,et al.  CpG-binding Protein Is a Nuclear Matrix- and Euchromatin-associated Protein Localized to Nuclear Speckles Containing Human Trithorax , 2002, The Journal of Biological Chemistry.

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

[113]  Kristian Helin,et al.  Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. , 2006, Genes & development.

[114]  Francisco Antequera,et al.  CpG islands as genomic footprints of promoters that are associated with replication origins , 1999, Current Biology.

[115]  M. Pellegrini,et al.  Conservation and divergence of methylation patterning in plants and animals , 2010, Proceedings of the National Academy of Sciences.