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DNA Methyltransferases: Facts, Clues, Mysteries

  • Chapter
DNA Methylation: Basic Mechanisms

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 301))

Abstract

DNA methylation plays a pivotal role during development in mammals and is central to transcriptional silencing. The DNA methyltransferases (DNMTs) are responsible for the generation of genomic methylation patterns leading to gene silencing, but the underlying molecular basis remains largely shrouded in mystery. Here we review our current understanding of the mechanisms by which DNMTs repress transcription and how they are targeted to preferred DNA sequences. Emerging evidence points to an essential and intricate web of interactions between DNMTs and the chromatin environment in which they function. The recent identification of novel transcription factors recruiting the DNMTs may open new avenues of research into the origin of DNA methylation patterns. Thanks to these emerging clues, researchers have begun to lift the veil on the multi-faceted DNMTs, but there remains fascinating work ahead for whoever wants to fully understand DNMTs and their role in the mammalian cell.

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References

  • Ayyanathan K, Lechner MS, Bell P, Maul GG, Schultz DC, Yamada Y, Tanaka K, Torigoe K, Rauscher FJ 3rd (2003) Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev 17:1855–1869

    Article  CAS  PubMed  Google Scholar 

  • Becker PB, Horz W (2002) ATP-dependent nucleosome remodeling. Annu Rev Biochem 71:247–273

    Article  CAS  PubMed  Google Scholar 

  • Bender J (2004) Chromatin-based silencing mechanisms. Curr Opin Plant Biol 7:521–526

    Article  CAS  PubMed  Google Scholar 

  • Bestor T, Laudano A, Mattaliano R, Ingram V (1988) 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. J Mol Biol 203:971–983

    Article  CAS  PubMed  Google Scholar 

  • Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    Article  CAS  PubMed  Google Scholar 

  • Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99:451–454

    Article  CAS  PubMed  Google Scholar 

  • Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99

    CAS  PubMed  Google Scholar 

  • Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH (2001) Dnmt3L and the establishment of maternal genomic imprints. Science 294:2536–2539

    CAS  PubMed  Google Scholar 

  • Brenner C, Deplus R, Didelot C, Loriot A, Vire E, De Smet C, Gutierrez A, Danovi D, Bernard D, Boon T, Giuseppe Pelicci P, Amati B, Kouzarides T, de Launoit Y, Di Croce L, Fuks F (2005) Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J 24:336–346

    CAS  PubMed  Google Scholar 

  • Burgers WA, Fuks F, Kouzarides T (2002) DNA methyltransferases get connected to chromatin. Trends Genet 18:275–277

    Article  CAS  PubMed  Google Scholar 

  • Cervoni N, Szyf M (2001) Demethylase activity is directed by histone acetylation. J Biol Chem 276:40778–40787

    Article  CAS  PubMed  Google Scholar 

  • Chedin F, Lieber MR, Hsieh CL (2002) The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci U S A 99:16916–16921

    Article  CAS  PubMed  Google Scholar 

  • Chen T, Ueda Y, Xie S, Li E (2002) A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J Biol Chem 277:38746–38754

    CAS  PubMed  Google Scholar 

  • Chen T, Ueda Y, Dodge JE, Wang Z, Li E (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23:5594–5605

    CAS  PubMed  Google Scholar 

  • Chen T, Tsujimoto N, Li E (2004) The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol Cell Biol 24:9048–9058

    CAS  PubMed  Google Scholar 

  • Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (1997) Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target forp21WAF1. Science 277:1996–2000

    Article  CAS  PubMed  Google Scholar 

  • Dennis K, Fan T, Geiman T, Yan Q, Muegge K (2001) Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev 15:2940–2944

    Article  CAS  PubMed  Google Scholar 

  • Deplus R, Brenner C, Burgers WA, Putmans P, Kouzarides T, de Launoit Y, Fuks F (2002) Dnmt3L is a transcriptional repressor that recruits histone deacetylase. Nucleic Acids Res 30:3831–3838

    Article  CAS  PubMed  Google Scholar 

  • Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295:1079–1082

    PubMed  Google Scholar 

  • Doherty AS, Bartolomei MS, Schultz RM (2002) Regulation of stage-specific nuclear translocation of Dnmt1o during preimplantation mouse development. Dev Biol 242:255–266

    Article  CAS  PubMed  Google Scholar 

  • Freitag M, Lee DW, Kothe GO, Pratt RJ, Aramayo R, Selker EU (2004) DNA methylation is independent of RNA interference in Neurospora. Science 304:1939

    Article  CAS  PubMed  Google Scholar 

  • Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003a) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–2312

    Article  CAS  PubMed  Google Scholar 

  • Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003b) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278:4035–4040

    Article  CAS  PubMed  Google Scholar 

  • Ge YZ, Pu MT, Gowher H, Wu HP, Ding JP, Jeltsch A, Xu GL (2004) Chromatin targeting of de novo DNA methyltransferases by the PWWP domain. J Biol Chem 279:25447–25454

    CAS  PubMed  Google Scholar 

  • Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Robertson KD (2004) DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system. Biochem Biophys Res Commun 318:544–555

    Article  CAS  PubMed  Google Scholar 

  • Gibbons RJ, McDowell TL, Raman S, O’Rourke DM, Garrick D, Ayyub H, Higgs DR (2000) Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet 24:368–371

    CAS  PubMed  Google Scholar 

  • Hata K, Okano M, Lei H, Li E (2002) Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129:1983–1993

    CAS  PubMed  Google Scholar 

  • Hermann A, Schmitt S, Jeltsch A (2003) The human Dnmt2 has residual DNA-(cytosine-C5) methyltransferase activity. J Biol Chem 278:31717–31721

    Article  CAS  PubMed  Google Scholar 

  • Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Chaillet JR (2001) Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104:829–838

    Article  CAS  PubMed  Google Scholar 

  • Hsieh CL (1999) In vivo activity of murine de novo methyltransferases, Dnmt3a and Dnmt3b. Mol Cell Biol 19:8211–8218

    CAS  PubMed  Google Scholar 

  • Jackson JP, Lindroth AM, Cao X, Jacobsen SE (2002) Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416:556–560

    Article  CAS  PubMed  Google Scholar 

  • Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33Suppl:245–254

    CAS  PubMed  Google Scholar 

  • Jeffery L, Nakielny S (2004) Components of the DNA methylation system of chromatin control are RNA-binding proteins. J Biol Chem 279:49479–49487

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  CAS  PubMed  Google Scholar 

  • Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191

    Article  CAS  PubMed  Google Scholar 

  • Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429:900–903

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki H, Taira K (2004) Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 431:211–217

    CAS  PubMed  Google Scholar 

  • Kurdistani SK, Grunstein M (2003) Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol 4:276–284

    Article  CAS  PubMed  Google Scholar 

  • Lee JT, Lu N (1999) Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99:47–57

    CAS  PubMed  Google Scholar 

  • Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (2003) Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13:1192–1200

    Article  CAS  PubMed  Google Scholar 

  • Leonhardt H, Page AW, Weier HU, Bestor TH (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865–873

    Article  CAS  PubMed  Google Scholar 

  • Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3:662–673

    Article  CAS  PubMed  Google Scholar 

  • Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926

    CAS  PubMed  Google Scholar 

  • Maison C, Bailly D, Peters AH, Quivy JP, Roche D, Taddei A, Lachner M, Jenuwein T, Almouzni G (2002) Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nat Genet 30:329–334

    Article  PubMed  Google Scholar 

  • Matzke MA, Birchler JA (2005) RNAi-mediated pathways in the nucleus. Nat Rev Genet 6:24–35

    Article  CAS  PubMed  Google Scholar 

  • Meehan RR, Stancheva I (2001) DNA methylation and control of gene expression in vertebrate development. Essays Biochem 37:59–70

    CAS  PubMed  Google Scholar 

  • Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH (1998) Sex-specific exons control DNA methyltransferase in mammalian germ cells. Development 125:889–897

    CAS  PubMed  Google Scholar 

  • Morris KV, Chan SW, Jacobsen SE, Looney DJ (2004) Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305:1289–1292

    CAS  PubMed  Google Scholar 

  • Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389

    CAS  PubMed  Google Scholar 

  • Okano M, Xie S, Li E (1998a) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19:219–220

    CAS  PubMed  Google Scholar 

  • Okano M, Xie S, Li E (1998b) Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stemcells. Nucleic Acids Res 26:2536–2540

    Article  CAS  PubMed  Google Scholar 

  • Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257

    Article  CAS  PubMed  Google Scholar 

  • Qiu C, Sawada K, Zhang X, Cheng X (2002) The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nat Struct Biol 9:217–224

    CAS  PubMed  Google Scholar 

  • Razin A, Cedar H (1977) Distribution of 5-methylcytosine in chromatin. Proc Natl Acad Sci U S A 74:2725–2728

    CAS  PubMed  Google Scholar 

  • Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406:593–599

    CAS  PubMed  Google Scholar 

  • Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB, Schuebel KE (2000) CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404:1003–1007

    CAS  PubMed  Google Scholar 

  • Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, Cui H, Feinberg AP, Lengauer C, Kinzler KW, Baylin SB, Vogelstein B (2002) DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416:552–556

    Article  CAS  PubMed  Google Scholar 

  • Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new corepressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269–277

    Article  CAS  PubMed  Google Scholar 

  • Sarraf SA, Stancheva I (2004) Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol Cell 15:595–605

    Article  CAS  PubMed  Google Scholar 

  • Selker EU (1998) Trichostatin A causes selective loss of DNA methylation in Neurospora. Proc Natl Acad Sci U S A 95:9430–9435

    Article  CAS  PubMed  Google Scholar 

  • Selker EU, Tountas NA, Cross SH, Margolin BS, Murphy JG, Bird AP, Freitag M (2003) The methylated component of the Neurospora crassa genome. Nature 422:893–897

    Article  CAS  PubMed  Google Scholar 

  • Soppe WJ, Jasencakova Z, Houben A, Kakutani T, Meister A, Huang MS, Jacobsen SE, Schubert I, Fransz PF (2002) DNA methylation controls histoneH3 lysine 9 methylation and heterochromatin assembly in Arabidopsis. EMBO J 21:6549–6559

    Article  CAS  PubMed  Google Scholar 

  • Stec I, Nagl SB, van Ommen GJ, den Dunnen JT (2000) The PWWP domain: a potential protein-protein interaction domain in nuclear proteins influencing differentiation? FEBS Lett 473:1–5

    Article  CAS  PubMed  Google Scholar 

  • Svoboda P, Stein P, Filipowicz W, Schultz RM (2004) Lack of homologous sequence-specific DNA methylation in response to stable dsRNA expression in mouse oocytes. Nucleic Acids Res 32:3601–3606

    Article  CAS  PubMed  Google Scholar 

  • Ting AH, Jair KW, Suzuki H, Yen RW, Baylin SB, Schuebel KE (2004) CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1. Nat Genet 36:582–584

    Article  CAS  PubMed  Google Scholar 

  • Tufarelli C, Stanley JA, Garrick D, Sharpe JA, Ayyub H, Wood WG, Higgs DR (2003) Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 34:157–165

    Article  CAS  PubMed  Google Scholar 

  • Xin Z, Tachibana M, Guggiari M, Heard E, Shinkai Y, Wagstaff J (2003) Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center. J Biol Chem 278:14996–15000

    Article  CAS  PubMed  Google Scholar 

  • Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402:187–191

    Article  CAS  PubMed  Google Scholar 

  • Yen RW, Vertino PM, Nelkin BD, Yu JJ, el-Deiry W, Cumaraswamy A, Lennon GG, Trask BJ, Celano P, Baylin SB (1992) Isolation and characterization of the cDNA encoding human DNA methyltransferase. Nucleic Acids Res 20:2287–2291

    CAS  PubMed  Google Scholar 

  • Yoder JA, Bestor TH (1998) A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7:279–284

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Molecular Virology, Faculty of Medicine, Free University of Brussels, 808 route de Lennik, 1070, Brussels, Belgium

    C. Brenner & F. Fuks

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  1. C. Brenner
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  2. F. Fuks
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  1. Institut für Genetik, Universität zu Köln, Zülpicher Str. 47, 50674, Köln, Germany

    Walter Doerfler (Prof. Dr.) & Petra Böhm (Prof. Dr.) & 

  2. Institut für Klinische und Molekulare Virologie, Universität Erlangen, Schlossgarten 4, 91054, Erlangen, Germany

    Walter Doerfler (Prof. Dr.) (Prof. Dr.)

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Brenner, C., Fuks, F. (2006). DNA Methyltransferases: Facts, Clues, Mysteries. In: Doerfler, W., Böhm, P. (eds) DNA Methylation: Basic Mechanisms. Current Topics in Microbiology and Immunology, vol 301. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-31390-7_3

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