Regulation and function of DNA methylation in plants and animals

DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt piwi-interacting small RNAs. DNA methylation status is dynamically regulated by DNA methylation and demethylation reactions. In plants, active DNA demethylation relies on the repressor of silencing 1 family of bifunctional DNA glycosylases, which remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, initiating a base excision repair (BER) pathway. In animals, multiple mechanisms of active DNA demethylation have been proposed, including a deaminase- and DNA glycosylase-initiated BER pathway. New information concerning the effects of various histone modifications on the establishment and maintenance of DNA methylation has broadened our understanding of the regulation of DNA methylation. The function of DNA methylation in plants and animals is also discussed in this review.

[1]  Wendy Dean,et al.  Dynamic reprogramming of DNA methylation in the early mouse embryo. , 2002, Developmental biology.

[2]  David P. Kreil,et al.  RNA‐directed DNA methylation and plant development require an IWR1‐type transcription factor , 2010, EMBO reports.

[3]  R. Jaenisch,et al.  Chromosomal Instability and Tumors Promoted by DNA Hypomethylation , 2003, Science.

[4]  M. Lieber,et al.  The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[6]  Julie A. Law,et al.  SRA-Domain Proteins Required for DRM2-Mediated De Novo DNA Methylation , 2008, PLoS genetics.

[7]  V. Chandler,et al.  Differential chromatin structure within a tandem array 100 kb upstream of the maize b1 locus is associated with paramutation. , 2002, Genes & development.

[8]  Xiaoyu Zhang,et al.  Two-Step Recruitment of RNA-Directed DNA Methylation to Tandem Repeats , 2006, PLoS biology.

[9]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[10]  H. Leonhardt,et al.  Interactions within the mammalian DNA methyltransferase family , 2003, BMC Molecular Biology.

[11]  Ravi Sachidanandam,et al.  Developmentally Regulated piRNA Clusters Implicate MILI in Transposon Control , 2007, Science.

[12]  T. Tada,et al.  Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis , 2002, Mechanisms of Development.

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

[14]  G. Ming,et al.  Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis , 2009, Science.

[15]  Claire Picart,et al.  RNA‐directed DNA methylation requires an AGO4‐interacting member of the SPT5 elongation factor family , 2009, EMBO reports.

[16]  Yi Zhang,et al.  Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification , 2010, Nature.

[17]  Haifan Lin,et al.  The biogenesis and function of PIWI proteins and piRNAs: progress and prospect. , 2009, Annual review of cell and developmental biology.

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

[19]  Joshua P. White,et al.  An RNA-dependent RNA polymerase is required for paramutation in maize , 2006, Nature.

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

[21]  A. Fischer,et al.  Activation-Induced Cytidine Deaminase (AID) Deficiency Causes the Autosomal Recessive Form of the Hyper-IgM Syndrome (HIGM2) , 2000, Cell.

[22]  R. Jaenisch,et al.  Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development. , 2008, Genes & development.

[23]  W. Reik,et al.  Genomic imprinting: parental influence on the genome , 2001, Nature Reviews Genetics.

[24]  Xiaofeng Cao,et al.  ARGONAUTE4 Control of Locus-Specific siRNA Accumulation and DNA and Histone Methylation , 2003, Science.

[25]  A. Riggs,et al.  The Histone Methyltransferase SETDB1 and the DNA Methyltransferase DNMT3A Interact Directly and Localize to Promoters Silenced in Cancer Cells* , 2006, Journal of Biological Chemistry.

[26]  Craig S. Pikaard,et al.  An ARGONAUTE4-Containing Nuclear Processing Center Colocalized with Cajal Bodies in Arabidopsis thaliana , 2006, Cell.

[27]  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.

[28]  W. Edelmann,et al.  Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Robert A. Martienssen,et al.  Noncoding RNAs and Gene Silencing , 2007, Cell.

[30]  Steven Henikoff,et al.  Extensive Demethylation of Repetitive Elements During Seed Development Underlies Gene Imprinting , 2009, Science.

[31]  Marjori Matzke,et al.  Role of the DRM and CMT3 Methyltransferases in RNA-Directed DNA Methylation , 2003, Current Biology.

[32]  Tohru Kimura,et al.  Associations between PIWI proteins and TDRD1/MTR‐1 are critical for integrated subcellular localization in murine male germ cells , 2009, Genes to cells : devoted to molecular & cellular mechanisms.

[33]  Y. Matsui,et al.  Expression and intracellular localization of mouse Vasa-homologue protein during germ cell development , 2000, Mechanisms of Development.

[34]  V. Chandler,et al.  Chromatin conversations: mechanisms and implications of paramutation , 2004, Nature Reviews Genetics.

[35]  S. Jacobsen,et al.  A metastable DWARF1 epigenetic mutant affecting plant stature in rice , 2009, Proceedings of the National Academy of Sciences.

[36]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[37]  Jon Penterman,et al.  Genetic Interactions between DNA Demethylation and Methylation in Arabidopsis[OA] , 2007, Plant Physiology.

[38]  A. Feinberg,et al.  Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores , 2008, Nature Genetics.

[39]  S. Vigneau,et al.  Genomic imprinting mechanisms in mammals. , 2008, Mutation research.

[40]  M. Matzke,et al.  HDA6, a putative histone deacetylase needed to enhance DNA methylation induced by double‐stranded RNA , 2002, The EMBO journal.

[41]  C. Senner,et al.  Xist gene regulation at the onset of X inactivation. , 2009, Current opinion in genetics & development.

[42]  R. Lister,et al.  Highly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis , 2008, Cell.

[43]  Xianwu Zheng,et al.  Role of Arabidopsis AGO6 in siRNA accumulation, DNA methylation and transcriptional gene silencing , 2007, The EMBO journal.

[44]  P. Goyal,et al.  Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation , 2009, Epigenetics.

[45]  I. Henderson,et al.  Tandem repeats upstream of the Arabidopsis endogene SDC recruit non-CG DNA methylation and initiate siRNA spreading. , 2008, Genes & development.

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

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

[48]  O. Mathieu,et al.  Transgenerational Stability of the Arabidopsis Epigenome Is Coordinated by CG Methylation , 2007, Cell.

[49]  R. Kuick,et al.  ICF, An Immunodeficiency Syndrome: DNA Methyltransferase 3B Involvement, Chromosome Anomalies, and Gene Dysregulation , 2008, Autoimmunity.

[50]  A. Jeltsch,et al.  Mechanism of Stimulation of Catalytic Activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L* , 2005, Journal of Biological Chemistry.

[51]  C. Disteche,et al.  Dosage compensation in mammals: fine-tuning the expression of the X chromosome. , 2006, Genes & development.

[52]  H. Leonhardt,et al.  DNA Methyltransferase Is Actively Retained in the Cytoplasm during Early Development , 1999, The Journal of cell biology.

[53]  Thomas Franz,et al.  Loss of the Mili-interacting Tudor domain–containing protein-1 activates transposons and alters the Mili-associated small RNA profile , 2009, Nature Structural &Molecular Biology.

[54]  T. Honjo,et al.  Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme , 2000, Cell.

[55]  C. Pikaard,et al.  Plant Nuclear RNA Polymerase IV Mediates siRNA and DNA Methylation-Dependent Heterochromatin Formation , 2005, Cell.

[56]  Jörg D. Becker,et al.  Epigenetic Reprogramming and Small RNA Silencing of Transposable Elements in Pollen , 2009, Cell.

[57]  C. Pikaard,et al.  VIM1, a methylcytosine-binding protein required for centromeric heterochromatinization. , 2007, Genes & development.

[58]  Alexandra M. E. Jones,et al.  An atypical RNA polymerase involved in RNA silencing shares small subunits with RNA polymerase II , 2009, Nature Structural &Molecular Biology.

[59]  G. Pan,et al.  Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. , 2007, Cell stem cell.

[60]  Xianwu Zheng,et al.  ROS3 is an RNA-binding protein required for DNA demethylation in Arabidopsis , 2008, Nature.

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

[62]  Jonathan E. Dodge,et al.  Inactivation of Dnmt3b in Mouse Embryonic Fibroblasts Results in DNA Hypomethylation, Chromosomal Instability, and Spontaneous Immortalization* , 2005, Journal of Biological Chemistry.

[63]  M. Siegmann,et al.  5-methylcytosine-DNA glycosylase activity is present in a cloned G/T mismatch DNA glycosylase associated with the chicken embryo DNA demethylation complex. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  C. Pikaard,et al.  Noncoding Transcription by RNA Polymerase Pol IVb/Pol V Mediates Transcriptional Silencing of Overlapping and Adjacent Genes , 2008, Cell.

[65]  K. Erhard,et al.  Diversity of Pol IV Function Is Defined by Mutations at the Maize rmr7 Locus , 2009, PLoS genetics.

[66]  T. Pawson,et al.  Mouse Piwi interactome identifies binding mechanism of Tdrkh Tudor domain to arginine methylated Miwi , 2009, Proceedings of the National Academy of Sciences.

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

[68]  J. P. Jackson,et al.  Requirement of CHROMOMETHYLASE3 for Maintenance of CpXpG Methylation , 2001, Science.

[69]  T. Bestor,et al.  The Colorful History of Active DNA Demethylation , 2008, Cell.

[70]  Albert Jeltsch,et al.  Cyclical DNA methylation of a transcriptionally active promoter , 2008, Nature.

[71]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[72]  T. Mockler,et al.  IDN 1 and IDN 2 are required for de novo DNA methylation in Arabidopsis thaliana , 2009 .

[73]  C. Pikaard,et al.  Mechanisms of HDA6-mediated rRNA gene silencing: suppression of intergenic Pol II transcription and differential effects on maintenance versus siRNA-directed cytosine methylation. , 2010, Genes & development.

[74]  T. Bestor,et al.  DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. , 1997, Journal of molecular biology.

[75]  Louise Jones,et al.  RNA-directed transcriptional gene silencing in plants can be inherited independently of the RNA trigger and requires Met1 for maintenance , 2001, Current Biology.

[76]  Paul Tempst,et al.  The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36 , 2006, Nature.

[77]  Yukihide Tomari,et al.  piRNAs--the ancient hunters of genome invaders. , 2007, Genes & development.

[78]  Adam M. Gustafson,et al.  Genetic and Functional Diversification of Small RNA Pathways in Plants , 2004, PLoS biology.

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

[80]  S. Henikoff,et al.  Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription , 2007, Nature Genetics.

[81]  Yeonhee Choi,et al.  One-Way Control of FWA Imprinting in Arabidopsis Endosperm by DNA Methylation , 2004, Science.

[82]  Atif Shahab,et al.  Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. , 2007, Cell stem cell.

[83]  E. Olson,et al.  MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs , 2010, Proceedings of the National Academy of Sciences.

[84]  Daisuke Hattori,et al.  DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation , 2003, Science.

[85]  Hailing Jin,et al.  An Effector of RNA-Directed DNA Methylation in Arabidopsis Is an ARGONAUTE 4- and RNA-Binding Protein , 2009, Cell.

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

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

[88]  En Li,et al.  Structure and function of eukaryotic DNA methyltransferases. , 2004, Current topics in developmental biology.

[89]  S. Jacobsen,et al.  The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix , 2008, Nature.

[90]  Y. Kohara,et al.  Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. , 2007, Human molecular genetics.

[91]  M. Surani,et al.  Epigenetic reprogramming in mouse primordial germ cells , 2002, Mechanisms of Development.

[92]  J. Feijó,et al.  Gene Family Analysis of the Arabidopsis Pollen Transcriptome Reveals Biological Implications for Cell Growth, Division Control, and Gene Expression Regulation1[w] , 2005, Plant Physiology.

[93]  G. Hannon,et al.  The Piwi-piRNA Pathway Provides an Adaptive Defense in the Transposon Arms Race , 2007, Science.

[94]  Paul A. Khavari,et al.  DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue , 2010, Nature.

[95]  H. Ng,et al.  Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. , 1997, Science.

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

[97]  Li Zhang,et al.  Genome-Wide Profiling of DNA Methylation Reveals a Class of Normally Methylated CpG Island Promoters , 2007, PLoS genetics.

[98]  Jian‐Kang Zhu Epigenome Sequencing Comes of Age , 2008, Cell.

[99]  R. R. Ariza,et al.  ROS1, a Repressor of Transcriptional Gene Silencing in Arabidopsis, Encodes a DNA Glycosylase/Lyase , 2002, Cell.

[100]  D. Gold,et al.  Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation , 2008, Nature Genetics.

[101]  Sudesh Kumar Yadav,et al.  An SGS3-like protein functions in RNA-directed DNA methylation and transcriptional gene silencing in Arabidopsis. , 2010, The Plant journal : for cell and molecular biology.

[102]  E. Li,et al.  KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints , 2009, Nature.

[103]  E. Li,et al.  Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells , 2007, Nature Genetics.

[104]  Karl Mechtler,et al.  Loss of the Suv39h Histone Methyltransferases Impairs Mammalian Heterochromatin and Genome Stability , 2001, Cell.

[105]  S. Jacobsen,et al.  The Arabidopsis Chromatin-Modifying Nuclear siRNA Pathway Involves a Nucleolar RNA Processing Center , 2006, Cell.

[106]  M. Ishitani,et al.  Genetic analysis of osmotic and cold stress signal transduction in Arabidopsis: interactions and convergence of abscisic acid-dependent and abscisic acid-independent pathways. , 1997, The Plant cell.

[107]  Paul Tempst,et al.  JHDM2A, a JmjC-Containing H3K9 Demethylase, Facilitates Transcription Activation by Androgen Receptor , 2006, Cell.

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

[109]  S. Inagaki,et al.  An Arabidopsis jmjC domain protein protects transcribed genes from DNA methylation at CHG sites , 2009, The EMBO journal.

[110]  Matthew Tudor,et al.  Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation , 2001, Nature Genetics.

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

[112]  Jianhua Zhu,et al.  NRPD4, a protein related to the RPB4 subunit of RNA polymerase II, is a component of RNA polymerases IV and V and is required for RNA-directed DNA methylation. , 2009, Genes & development.

[113]  G. Ming,et al.  G9a and Jhdm2a Regulate Embryonic Stem Cell Fusion‐Induced Reprogramming of Adult Neural Stem Cells , 2008, Stem cells.

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

[115]  F. Ding,et al.  Genomic Imprinting Disrupted by a Maternal Effect Mutation in the Dnmt1 Gene , 2001, Cell.

[116]  Jianjun Zhu,et al.  Control of DNA methylation and heterochromatic silencing by histone H2B deubiquitination , 2007, Nature.

[117]  C. Arrowsmith,et al.  Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1 , 2008, Nature.

[118]  K. Struhl,et al.  The transition from transcriptional initiation to elongation. , 2008, Current opinion in genetics & development.

[119]  Jianhua Zhu,et al.  The DNA Glycosylase/Lyase ROS1 Functions in Pruning DNA Methylation Patterns in Arabidopsis , 2007, Current Biology.

[120]  Kenichiro Hata,et al.  DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. , 2008, Genes & development.

[121]  Yoichi Matsuda,et al.  Mili, a mammalian member of piwi family gene, is essential for spermatogenesis , 2004, Development.

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

[123]  J. P. Jackson,et al.  The late flowering phenotype of fwa mutants is caused by gain-of-function epigenetic alleles of a homeodomain gene. , 2000, Molecular cell.

[124]  Yi Zhang,et al.  Active DNA demethylation: many roads lead to Rome , 2010, Nature Reviews Molecular Cell Biology.

[125]  B. Ramsahoye,et al.  DNA methylation in mouse embryonic stem cells and development , 2007, Cell and Tissue Research.

[126]  G. Hannon,et al.  MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. , 2007, Developmental cell.

[127]  J. Poulain,et al.  A Role for RNAi in the Selective Correction of DNA Methylation Defects , 2009, Science.

[128]  D. Baulcombe,et al.  An SNF2 Protein Associated with Nuclear RNA Silencing and the Spread of a Silencing Signal between Cells in Arabidopsis[W][OA] , 2007, The Plant Cell Online.

[129]  P. Borst,et al.  Base J: discovery, biosynthesis, and possible functions. , 2008, Annual review of microbiology.

[130]  J. P. Jackson,et al.  Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase , 2002, Nature.

[131]  T. Kanno,et al.  PolV(PolIVb) function in RNA-directed DNA methylation requires the conserved active site and an additional plant-specific subunit , 2009, Proceedings of the National Academy of Sciences.

[132]  D. Weigel,et al.  Selective epigenetic control of retrotransposition in Arabidopsis , 2009, Nature.

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

[134]  Charles W. Melnyk,et al.  JMJ14, a JmjC domain protein, is required for RNA silencing and cell-to-cell movement of an RNA silencing signal in Arabidopsis. , 2010, Genes & development.

[135]  M Plachot,et al.  Chromosome methylation patterns during mammalian preimplantation development. , 1998, Genes & development.

[136]  Rudolf Jaenisch,et al.  Role for DNA methylation in genomic imprinting , 1993, Nature.

[137]  Xuemei Chen,et al.  Intergenic transcription by RNA polymerase II coordinates Pol IV and Pol V in siRNA-directed transcriptional gene silencing in Arabidopsis. , 2009, Genes & development.

[138]  Julie A. Law,et al.  Establishing, maintaining and modifying DNA methylation patterns in plants and animals , 2010, Nature Reviews Genetics.

[139]  Catherine Dulac Brain function and chromatin plasticity , 2010, Nature.

[140]  Vladimir Benes,et al.  Transient cyclical methylation of promoter DNA , 2008, Nature.

[141]  Songgang Li,et al.  High-Resolution Mapping of Epigenetic Modifications of the Rice Genome Uncovers Interplay between DNA Methylation, Histone Methylation, and Gene Expression[W] , 2008, The Plant Cell Online.

[142]  T. Kakutani,et al.  Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis , 2001, Nature.

[143]  David P. Kreil,et al.  A structural-maintenance-of-chromosomes hinge domain–containing protein is required for RNA-directed DNA methylation , 2008, Nature Genetics.

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

[145]  M. Matzke,et al.  Endogenous targets of RNA‐directed DNA methylation and Pol IV in Arabidopsis , 2006, The EMBO journal.

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

[147]  N. Tsunekawa,et al.  Vasa homolog genes in mammalian germ cell development. , 2001, Cell structure and function.

[148]  R. Hausinger,et al.  The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase , 2007, Nucleic acids research.

[149]  Ravi Sachidanandam,et al.  A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. , 2008, Molecular cell.

[150]  S. Jacobsen,et al.  DEMETER, a DNA Glycosylase Domain Protein, Is Required for Endosperm Gene Imprinting and Seed Viability in Arabidopsis , 2002, Cell.

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

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

[153]  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 .

[154]  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.

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

[156]  Christof Niehrs,et al.  Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation , 2007, Nature.

[157]  Albert Jeltsch,et al.  Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail , 2010, Nucleic acids research.

[158]  D. Baulcombe,et al.  RNA Polymerase IV Directs Silencing of Endogenous DNA , 2005, Science.

[159]  J. Arand,et al.  Epigenetic Reprogramming in Mammalian Development , 2012 .

[160]  T. Kakutani,et al.  Bursts of retrotransposition reproduced in Arabidopsis , 2009, Nature.

[161]  C. Pikaard,et al.  RNA Polymerase V transcription guides ARGONAUTE4 to chromatin , 2009, Nature Genetics.

[162]  G. Ming,et al.  G 9 a and Jhdm 2 a Regulate Embryonic Stem Cell Fusion-Induced Reprogramming of Adult Neural Stem Cells , 2008 .

[163]  R J Roberts,et al.  Recombinant Human DNA (Cytosine-5) Methyltransferase , 1999, The Journal of Biological Chemistry.

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

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

[166]  R. Jaenisch,et al.  Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[167]  L. Paša-Tolić,et al.  Subunit compositions of the RNA-silencing enzymes Pol IV and Pol V reveal their origins as specialized forms of RNA polymerase II. , 2009, Molecular cell.

[168]  W. Johnson,et al.  DNA Demethylase Activity Maintains Intestinal Cells in an Undifferentiated State Following Loss of APC , 2010, Cell.

[169]  T. Haaf Methylation dynamics in the early mammalian embryo: implications of genome reprogramming defects for development. , 2006, Current topics in microbiology and immunology.

[170]  C. Walsh,et al.  Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair , 2006, Nucleic acids research.

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

[172]  T. Jenuwein,et al.  Dual histone H3 methylation marks at lysines 9 and 27 required for interaction with CHROMOMETHYLASE3 , 2004, The EMBO journal.

[173]  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.

[174]  David P. Kreil,et al.  Atypical RNA polymerase subunits required for RNA-directed DNA methylation , 2005, Nature Genetics.

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

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

[177]  U. Grossniklaus,et al.  The Arabidopsis thaliana MEDEA Polycomb group protein controls expression of PHERES1 by parental imprinting , 2005, Nature Genetics.

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

[179]  V. Colot,et al.  Eukaryotic DNA methylation as an evolutionary device , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[180]  D. Smeets,et al.  ICF syndrome: a new case and review of the literature , 1994, Human Genetics.

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

[182]  Hye Ryun Woo,et al.  Three SRA-Domain Methylcytosine-Binding Proteins Cooperate to Maintain Global CpG Methylation and Epigenetic Silencing in Arabidopsis , 2008, PLoS genetics.

[183]  M. Pellegrini,et al.  Genome-wide High-Resolution Mapping and Functional Analysis of DNA Methylation in Arabidopsis , 2006, Cell.

[184]  J. Christman,et al.  Characterization of Dnmt3b:thymine-DNA glycosylase interaction and stimulation of thymine glycosylase-mediated repair by DNA methyltransferase(s) and RNA. , 2008, Journal of molecular biology.

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

[186]  Krystyna A. Kelly,et al.  Uniparental expression of PolIV-dependent siRNAs in developing endosperm of Arabidopsis , 2009, Nature.

[187]  Julie A. Law,et al.  A Protein Complex Required for Polymerase V Transcripts and RNA- Directed DNA Methylation in Arabidopsis , 2010, Current Biology.

[188]  A. Fujiyama,et al.  MVH in piRNA processing and gene silencing of retrotransposons. , 2010, Genes & development.

[189]  I. Henderson,et al.  The SRA Methyl-Cytosine-Binding Domain Links DNA and Histone Methylation , 2007, Current Biology.

[190]  G. Kelsey,et al.  Transcription is required for establishment of germline methylation marks at imprinted genes. , 2009, Genes & development.

[191]  S. Dellaporta,et al.  Demethylation-Induced Developmental Pleiotropy in Arabidopsis , 1996, Science.

[192]  Jianhua Zhu,et al.  A conserved transcriptional regulator is required for RNA-directed DNA methylation and plant development. , 2009, Genes & development.

[193]  T. Kakutani,et al.  Control of FWA gene silencing in Arabidopsis thaliana by SINE-related direct repeats. , 2006, The Plant journal : for cell and molecular biology.

[194]  E. Li,et al.  Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. , 2002, Development.

[195]  T. Bestor,et al.  Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L , 2004, Nature.

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

[197]  Hong Duan,et al.  Role for DNA methylation in the control of cell type–specific maspin expression , 2002, Nature Genetics.

[198]  R. R. Ariza,et al.  DEMETER and REPRESSOR OF SILENCING 1 encode 5-methylcytosine DNA glycosylases. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[199]  H. L. Sänger,et al.  RNA-directed de novo methylation of genomic sequences in plants , 1994, Cell.

[200]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[201]  S. Henikoff,et al.  DNA demethylation in the Arabidopsis genome , 2007, Proceedings of the National Academy of Sciences.

[202]  Jon Penterman,et al.  DEMETER DNA Glycosylase Establishes MEDEA Polycomb Gene Self-Imprinting by Allele-Specific Demethylation , 2006, Cell.

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

[204]  Yi Zhang,et al.  Dnmt3a-Dependent Nonpromoter DNA Methylation Facilitates Transcription of Neurogenic Genes , 2010, Science.

[205]  C. Pikaard,et al.  Heterochromatic siRNAs and DDM1 Independently Silence Aberrant 5S rDNA Transcripts in Arabidopsis , 2009, PloS one.

[206]  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.

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

[208]  J. Paszkowski,et al.  Maintenance of CpG methylation is essential for epigenetic inheritance during plant gametogenesis , 2003, Nature Genetics.

[209]  I. Suetake,et al.  DNMT3L Stimulates the DNA Methylation Activity of Dnmt3a and Dnmt3b through a Direct Interaction* , 2004, Journal of Biological Chemistry.

[210]  W. Edelmann,et al.  Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[211]  M. Surani,et al.  Genome-Wide Reprogramming in the Mouse Germ Line Entails the Base Excision Repair Pathway , 2010, Science.

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

[213]  David P. Kreil,et al.  Involvement of Putative SNF2 Chromatin Remodeling Protein DRD1 in RNA-Directed DNA Methylation , 2004, Current Biology.

[214]  D. Baulcombe,et al.  PolIVb influences RNA-directed DNA methylation independently of its role in siRNA biogenesis , 2008, Proceedings of the National Academy of Sciences.

[215]  T. Kakutani,et al.  Heritable epigenetic mutation of a transposon‐flanked Arabidopsis gene due to lack of the chromatin‐remodeling factor DDM1 , 2007, The EMBO journal.

[216]  T. Bestor,et al.  Properties and localization of DNA methyltransferase in preimplantation mouse embryos: implications for genomic imprinting. , 1992, Genes & development.

[217]  I. Henderson,et al.  Epigenetic inheritance in plants , 2007, Nature.

[218]  Haifan Lin,et al.  Mili Interacts with Tudor Domain-Containing Protein 1 in Regulating Spermatogenesis , 2009, Current Biology.

[219]  R. Kornberg The molecular basis of eukaryotic transcription , 2007, Proceedings of the National Academy of Sciences.

[220]  F. Ledeist,et al.  An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. , 1993, Human molecular genetics.

[221]  E. Li,et al.  Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting , 2004, Nature.

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

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

[224]  Jian-Kang Zhu,et al.  RNA-directed DNA methylation and demethylation in plants , 2009, Science in China Series C: Life Sciences.

[225]  R. Sachidanandam,et al.  Mouse MOV10L1 associates with Piwi proteins and is an essential component of the Piwi-interacting RNA (piRNA) pathway , 2010, Proceedings of the National Academy of Sciences.

[226]  C. Wijmenga,et al.  The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[228]  Xuemei Chen,et al.  Methylation as a Crucial Step in Plant microRNA Biogenesis , 2005, Science.

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

[230]  Patrick Cramer,et al.  Multisubunit RNA polymerases. , 2002, Current opinion in structural biology.

[231]  Xiaodong Cheng,et al.  Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation , 2007, Nature.

[232]  R. Jaenisch,et al.  De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. , 1996, Development.

[233]  Jian-Kang Zhu,et al.  Role of the Arabidopsis DNA glycosylase/lyase ROS1 in active DNA demethylation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[234]  Michael Weber,et al.  Genomic patterns of DNA methylation: targets and function of an epigenetic mark. , 2007, Current opinion in cell biology.

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

[236]  M. Belfort,et al.  The take and give between retrotransposable elements and their hosts. , 2008, Annual review of genetics.

[237]  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.

[238]  J. B. Hollick,et al.  Maize sex determination and abaxial leaf fates are canalized by a factor that maintains repressed epigenetic states. , 2007, Developmental biology.

[239]  S. Lerbs-Mache,et al.  Reinforcement of silencing at transposons and highly repeated sequences requires the concerted action of two distinct RNA polymerases IV in Arabidopsis. , 2005, Genes & development.

[240]  R. Sachidanandam,et al.  Proteomic analysis of murine Piwi proteins reveals a role for arginine methylation in specifying interaction with Tudor family members. , 2009, Genes & development.

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

[242]  M. Siegmann,et al.  Mechanisms of DNA Demethylation in Chicken Embryos , 1995, The Journal of Biological Chemistry.

[243]  A. Bird,et al.  Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[244]  Christopher J. Hale,et al.  RNA Polymerase IV Functions in Paramutation in Zea mays , 2009, Science.

[245]  HEN1 recognizes 21–24 nt small RNA duplexes and deposits a methyl group onto the 2′ OH of the 3′ terminal nucleotide , 2006, Nucleic acids research.

[246]  Nir Ohad,et al.  Polycomb Group Complexes Self-Regulate Imprinting of the Polycomb Group Gene MEDEA in Arabidopsis , 2006, Current Biology.

[247]  Yi Zhang,et al.  A role for elongator in zygotic paternal genome demethylation , 2010, Nature.

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

[249]  T. Kakutani,et al.  Control of Genic DNA Methylation by a jmjC Domain-Containing Protein in Arabidopsis thaliana , 2008, Science.

[250]  Ronald H. Schwartz,et al.  Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process , 2003, Nature Immunology.

[251]  S. Henikoff,et al.  Locus-specific control of asymmetric and CpNpG methylation by the DRM and CMT3 methyltransferase genes , 2002 .

[252]  Marcos J. Araúzo-Bravo,et al.  Direct reprogramming of human neural stem cells by OCT4 , 2009, Nature.

[253]  M. Marshall,et al.  JBP1 and JBP2 are two distinct thymidine hydroxylases involved in J biosynthesis in genomic DNA of African trypanosomes , 2009, Nucleic acids research.

[254]  Hailing Jin,et al.  An RNA polymerase II- and AGO4-associated protein acts in RNA-directed DNA methylation , 2010, Nature.

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