Abstract
In mammals, more than 70 % of the CpG sequences in the genome are methylated at the 5th position of cytosine bases. DNA methylation acts as a regulator of gene expression and is crucial for development, especially in higher eukaryotes. In mammals, three DNA (cytosine-5-)-methyltransferases, Dnmt1, Dnmt3a, and Dnmt3b, have been identified. Dnmt3a and Dnmt3b are mainly responsible for establishing DNA methylation patterns in the genome. For the establishment of DNA methylation patterns, interacting or associating factors that take Dnmt3a or Dnmt3b to the site of methylation, the timing of expression, and the substrate DNA with higher ordered structures (chromatin states) are the determinants. Dnmt1 favors methylation of hemi-methylated DNA, which appears just after replication or repair, and thus is responsible for maintaining the methylation patterns during replication and after repair. Recently, it was found that Uhrf1 and histone ubiquitylation are necessary factors for maintenance DNA methylation in vivo. In this chapter, the establishment and maintenance of DNA methylation by Dnmt3a, Dnmt3b, and Dnmt1 are described.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aapola U, Kawasaki K, Scott HS, Ollila J, Vihinen M, Heino M, Shintani A, Kawasaki K, Minoshima S, Krohn K, Antonarakis SE, Shimizu N, Kudoh J, Peterson P (2000) Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65:293–298
Alabert C, Bukowski-Wills JC, Lee SB, Kustatscher G, Nakamura K, de Lima AF, Menard P, Mejlvang J, Rappsilber J, Groth A (2014) Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nat Cell Biol 16:281–293
Allan AM, Liang X, Luo Y, Pak C, Li X, Szulwach KE, Chen D, Jin P, Zhao X (2008) The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum Mol Genet 17:2047–2057
Aoki A, Suetake I, Miyagawa J, Fujio T, Chijiwa T, Sasaki H, Tajima S (2001) Enzymatic properties of de novo-type mouse DNA (cytosine-5) methyltransferases. Nucleic Acids Res 29:3506–3512
Arand J, Spieler D, Karius T, Branco MR, Meilinger D, Meissner A, Jenuwein T, Xu G, Leonhardt H, Wolf V, Walter J (2012) In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet 8, e1002750
Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M (2008) Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455:818–821
Arita K, Isogai S, Oda T, Unoki M, Sugita K, Sekiyama N, Kuwata K, Hamamoto R, Tochio H, Sato M, Ariyoshi M, Shirakawa M (2012) Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc Natl Acad Sci USA 109:12950–12955
Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, Arrowsmith CH, Dhe-Paganon S (2008) Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455:822–825
Bell AC, Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485
Berkyurek AC, Suetake I, Arita K, Takeshita K, Nakagawa A, Shirakawa M, Tajima S (2014) The DNA methyltransferase Dnmt1 directly interacts with the SET and RING finger associated (SRA) domain of the multifunctional protein Uhrf1 to facilitate accession of the catalytic center to hemi-methylated DNA. J Biol Chem 289:379–386
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
Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D, Mastrangelo MA, Jun Z, Walter J, Jaenisch R (2002) Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol 22:2124–2135
Bird AP (1995) Gene number, noise reduction and biological complexity. Trends Genet 11:94–100
Bird AP (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21
Bostick M, Kim JK, Estève PO, Clark A, Pradhan S, Jacobsen SE (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317:1760–1764
Bourc’his D, Xu G, Lin C, Bollman B, Bestor TH (2001) Dnmt3L and establishment of maternal genomic imprints. Science 294:2536–2539
Brenner C, Deplus R, Didelot C, Loriot A, Viré E, De Smet C, Gutierrez A, Danovi D, Bernard D, Boon T, Pelicci PG, 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
Capuano F, Mülleder M, Kok R, Blom HJ, Ralser M (2014) Cytosine DNA methylation is found in Drosophila melanogaster but absent in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and other yeast species. Anal Chem 86:3697–3702
Catez F, Ueda T, Bustin M (2006) Determinants of histone H1 mobility and chromatin binding in living cells. Nat Struct Mol Biol 13:305–310
Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331
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
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
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
Chen ZX, Mann JR, Hsieh CL, Riggs AD, Chédin F (2005) Physical and functional interactions between the human DNMT3L protein and members of the de novo methyltransferase family. J Cell Biochem 95:902–917
Christman JK, Sheikhnejad G, Marasco CJ, Sufrin JR (1995) 5-Methyl-2′-deoxycytidine in single-stranded DNA can act in cis to signal de novo DNA methylation. Proc Natl Acad Sci USA 92:7347–7351
Chuang LSH, Ian H, Koh T, Ng H, Xu G, Li BFL (1997) Human DNA-(cytosine-5) methyltransferase PCNA complex as a target for p21WAF1. Science 277:1996–2000
Datta J, Majumder S, Bai S, Ghoshal K, Kutay H, Smith DS, Crabb JW, Jacob ST (2005) Physical and functional interaction of DNA methyltransferase 3A with Mbd3 and Brg1 in mouse lymphosarcoma cells. Cancer Res 65:10891–10900
Defossez PA, Stancheva I (2011) Biological functions of methyl-CpG-binding proteins. Prog Mol Biol Transl Sci 101:377–397
Dhayalan A, Rajavelu A, Rathert P, Tamas R, Jurkowska RZ, Ragozin S, Jeltsch A (2010) The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J Biol Chem 285:26114–26120
Diez CM, Roessler K, Gaut BS (2014) Epigenetics and plant genome evolution. Curr Opin Plant Biol 18:1–8
Dodge JE, Okano M, Dick F, Tsujimoto N, Chen T, Wang S, Ueda Y, Dyson N, Li E (2005) Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J Biol Chem 280:17986–17991
El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE (2008) G9a and HP1 couple histone and DNA methylation to TNFα transcription silencing during endotoxin tolerance. J Biol Chem 283:32198–33208
Estève PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MF, Pradhan S (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20:3089–3103
Estève PO, Chang Y, Samaranayake M, Upadhyay AK, Horton JR, Feehery GR, Cheng X, Pradhan S (2011) A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nat Struct Mol Biol 18:42–48
Fatemi M, Hermann A, Pradhan S, Jeltsch A (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J Mol Biol 309:1189–1199
Feng Q, Zhang Y (2001) The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes Dev 15:827–832
Fu Y, Luo GZ, Chen K, Deng X, Yu M, Han D, Hao Z, Liu J, Lu X, Doré LC, Weng X, Ji Q, Mets L, He C (2015) N6-methyldeoxyadenosine marks active transcription start sites in chlamydomonas. Cell 161:879–889
Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M (2003) Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J Biol Chem 278:24132–24138
Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T (2001) Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J 20:2536–2544
Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–2312
Garvilles RG, Hasegawa T, Kimura H, Sharif J, Muto M, Koseki H, Takahashi S, Suetake I, Tajima S (2015) Dual functions of the RFTS domain of Dnmt1 in replication-coupled DNA methylation and in protection of the genome from aberrant methylation. PLoS One 10, e0137509
Gaudet F, Talbot D, Leonhardt H, Jaenisch R (1998) A short DNA methyltransferase isoform restores methylation in vivo. J Biol Chem 273:32725–32729
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
Glastad KM, Hunt BG, Yi SV, Goodisman MAD (2011) DNA methylation in insects: on the brink of the epigenomic era. Insect Mol Biol 20:553–565
Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE, Bestor TH (2006) Methylation of tRNA Asp by the DNA methyltransferase homolog Dnmt2. Science 311:395–398
Gopalakrishnan S, Sullivan BA, Trazzi S, Della Valle G, Robertson KD (2009) DNMT3B interacts with constitutive centromere protein CENP-C to modulate DNA methylation and the histone code at centromeric regions. Hum Mol Genet 18:3178–3193
Gordon CA, Hartono SR, Chédin F (2013) Inactive DNMT3B splice variants modulate de novo DNA methylation. PLoS One 8, e69486
Gowher H, Leismann O, Jeltsch A (2000) DNA of Drosophila melanogaster contains 5-methylcytosine. EMBO J 19:6918–6923
Greer EL, Blanco MA, Gu L, Sendinc E, Liu J, Aristizábal-Corrales D, Hsu CH, Aravind L, He C, Shi Y (2015) DNA methylation on N6-adenine in C. elegans. Cell 161:868–878
Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, Zhong C, Hu S, Le T, Fan G, Zhu H, Chang Q, Gao Y, Ming GL, Song H (2014) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17:215–222
Guo X, Wang L, Li J, Ding Z, Xiao J, Yin X, He S, Shi P, Dong L, Li G, Tian C, Wang J, Cong Y, Xu Y (2015) Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517:640–644
Handa V, Jeltsch A (2005) Profound flanking sequence preference of Dnmt3a and Dnmt3b mammalian DNA methyltransferases shape the human epigenome. J Mol Biol 348:1103–1112
Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 96:14412–14417
Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405:486–489
Harrington MA, Jones PA, Imagawa M, Karin M (1988) Cytosine methylation does not affect binding of transcription factor Sp1. Proc Natl Acad Sci USA 85:2066–2070
Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE, Cheng X (2008) The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455:826–829
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
Hendrich B, Tweedie S (2003) The methyl-CpG binding domain and the evolving role of DNA methylation. Trends Genet 19:269–277
Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A (2001) Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev 15:710–723
Horii T, Suetake I, Yanagisawa E, Morita S, Kimura M, Nagao Y, Imai H, Tajima S, Hatada I (2011) The Dnmt3b splice variant is specifically expressed in in vitro-manipulated blastocysts and their derivative ES cells. J Reprod Dev 57:579–585
Hotchikiss RD (1948) The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem 175:315–332
Hu YG, Hirasawa R, Hu JL, Hata K, Li CL, Jin Y, Chen T, Li E, Rigolet M, Viegas-Péquignot E, Sasaki H, Xu GL (2008) Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development. Hum Mol Genet 17:2654–2664
Hutchins AS, Mullen AC, Lee HW, Sykes KJ, High FA, Hendrich BD, Bird AP, Reiner SL (2002) Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell 10:81–91
Inano K, Suetake I, Ueda T, Miyake Y, Nakamura M, Okada M, Tajima S (2000) Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem 128:315–321
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133
Iwano H, Nakamura M, Tajima S (2004) Xenopus MBD3 plays a crucial role in an early stage of development. Dev Biol 268:416–428
Jeddeloh JA, Stokes TL, Richards EJ (1999) Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nat Genet 22:94–97
Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X (2007) Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449:248–251
Kameshita I, Sekiguchi M, Hamasaki D, Sugiyama Y, Hatano N, Suetake I, Tajima S, Sueyoshi N (2008) Cyclin-dependent kinase-like 5 binds and phosphorylates DNA methyltransferase 1. Biochem Biophys Res Commun 377:1162–1167
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
Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002) Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J 21:4183–4195
Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, B Dyck PJ, Parisi JE, Mer G, Smith DI, Dyck PJ (2011) Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 43:595–600
Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502:472–479
Kucharski R, Maleszka J, Foret S, Maleszka R (2008) Nutritional control of reproductive status in honeybees via DNA methylation. Science 319:1827–1830
Kumar S, Cheng X, Klimasauskas S, Mi S, Posfai J, Roberts RJ, Wilson GG (1994) The DNA (cytosine-5) methyltransferases. Nucleic Acids Res 22:1–10
Lavoie G, St-Pierre Y (2011) Phosphorylation of human DNMT1: implication of cyclin-dependent kinases. Biochem Biophys Res Commun 409:187–192
Lavoie G, Estève PO, Laulan NB, Pradhan S, St-Pierre Y (2011) PKC isoforms interact with and phosphorylate DNMT1. BMC Biol 9:31
Leonhardt H, Page AW, Weier HU, Bestor TH (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865–8873
Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69:905–914
Li Y, Zhu B (2014) Acute myeloid leukemia with DNMT3A mutations. Leuk Lymphoma 55:2002–2012
Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926
Li BZ, Huang Z, Cui QY, Song XH, Du L, Jeltsch A, Chen P, Li G, Li E, Xu GL (2011) Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res 21:1172–1181
Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA (2002) Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 22:480–491
Lienert F, Wirbelauer C, Som I, Dean A, Mohn F, Schübeler D (2011) Identification of genetic elements that autonomously determine DNA methylation states. Nat Genet 43:1091–1097
Lin IG, Han L, Taghva A, O’Brien LE, Hsieh CL (2002) Murine de novo methyltransferase Dnmt3a demonstrates strand asymmetry and site preference in the methylation of DNA in vitro. Mol Cell Biol 22:704–723
Liu Y, Sun L, Jost JP (1996) In differentiating mouse myoblasts DNA methyltransferase is posttranscriptionally and posttranslationally regulated. Nucleic Acids Res 24:2718–2722
Liu Y, Zhang X, Blumenthal RM, Cheng X (2013) A common mode of recognition for methylated CpG. Trends Biochem Sci 38:177–183
Lorincz MC, Schübeler D, Hutchinson SR, Dickerson DR, Groudine M (2002) DNA methylation density influences the stability of an epigenetic imprint and Dnmt3a/b-independent de novo methylation. Mol Cell Biol 22:7572–7580
Lyko F, Ramsahoye BH, Jaenisch R (2000) DNA methylation in Drosophila melanogaster. Nature 408:538–540
Meissner A, Gnirke A, Bell GW, Ramsahoye B, Lander ES, Jaenisch R (2005) Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 33:5868–5877
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
Morales-Ruiz T, Ortega-Galisteo AP, Ponferrada-Marin MI, Martinez-Macıas MI, Ariza RR, Roldan-Arjona T (2006) DEMETER and REPRESSOR OF SILENCING 1 encode 5-methylcytosine DNA glycosylases. Proc Natl Acad Sci USA 103:6853–6858
Neri F, Krepelova A, Incarnato D, Maldotti M, Parlato C, Galvagni F, Matarese F, Stunnenberg HG, Oliviero S (2013) Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. Cell 155:121–134
Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A (1999) MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 23:58–61
Nishiyama A, Yamaguchi L, Sharif J, Johmura Y, Kawamura T, Nakanishi K, Shimamura S, Arita K, Kodama T, Ishikawa F, Koseki H, Nakanishi M (2013) Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 502:249–253
Noyer-Weidner M, Trautner TA (1993) Methylation of DNA in prokaryote. In: Jost JP, Saluz HP (eds) DNA methylation: molecular biology and biological significance. BirkHauser Verlag, Basel, pp 39–108
Ohki I, Shimotake N, Fujita N, Jee J, Ikegami T, Nakao M, Shirakawa M (2001) Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA. Cell 105:487–497
Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19:219–220
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
Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717
Ostler KR, Davis EM, Payne SL, Gosalia BB, Exposito-Cespedes J, Le Beau MM, Godley LA (2007) Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26:5553–5563
Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M (2009) Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep 10:1235–1241
Otani J, Arita K, Kato T, Kinoshita M, Kimura H, Suetake I, Tajima S, Ariyoshi M, Shirakawa M (2013a) Structural basis of the versatile DNA recognition ability of the methyl-CpG binding domain of methyl-CpG binding domain protein 4. J Biol Chem 288:6351–6362
Otani J, Kimura H, Sharif J, Endo TA, Mishima Y, Kawakami T, Koseki H, Shirakawa M, Suetake I, Tajima S (2013b) Cell cycle-dependent turnover of 5-hydroxymethyl cytosine in mouse embryonic stem cells. PLoS One 8, e82961
Pedroso JL, Povoas Barsottini OG, Lin L, Melberg A, Oliveira ASB, Mignot E (2013) A novel de novo exon 21 DNMT1 mutation causes cerebellar ataxia, deafness, and narcolepsy in a Brazilian patient. Sleep 36:1257–1259
Prendergast GC, Ziff EB (1991) Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science 251:186–189
Purdy MM, Holz-Schietinger C, Reich NO (2010) Identification of a second DNA binding site in human DNA methyltransferase 3A by substrate inhibition and domain deletion. Arch Biochem Biophys 498:13–22
Qin W, Wolf P, Liu N, Link S, Smets M, Mastra FL, Forné I, Pichler G, Hörl D, Fellinger K, Spada F, Bonapace IM, Imhof A, Harz H, Leonhardt H (2015) DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res 25:911–929
Qiu C, Sawada K, Zhang X, Cheng X (2002) The PWWP domain of mammalian DNA methyltrasnferase Dnmt3b defines a new family of DNA-binding fold. Nat Struct Biol 9:217–224
Quenneville S, Verde G, Corsinotti A, Kapopoulou A, Jakobsson J, Offner S, Baglivo I, Pedone PV, Grimaldi G, Riccio A, Trono D (2011) In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell 44:361–372
Quenneville S, Turelli P, Bojkowska K, Raclot C, Offner S, Kapopoulou A, Trono D (2012) The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development. Cell Rep 2:766–773
Riccio A, Aaltonen LA, Godwin AK, Loukola A, Percesepe A, Salovaara R, Masciullo V, Genuardi M, Paravatou-Petsotas M, Bassi DE, Ruggeri BA, Klein-Szanto AJ, Testa JR, Neri G, Bellacosa A (1999) The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability. Nat Genet 23:266–268
Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27:2291–2298
Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25:338–342
Robertson AK, Geiman TM, Sankpal UT, Hager GL, Robertson KD (2004) Effects of chromatin structure on the enzymatic and DNA binding functions of DNA methyltransferases DNMT1 and Dnmt3a in vitro. Biochem Biophys Res Commun 322:110–118
Ross JP, Suetake I, Tajima S, Molloy PL (2010) Recombinant mammalian DNA methyltransferase activity on model transcriptional gene silencing short RNA-DNA heteroduplex substrates. Biochem J 432:323–332
Rothbart SB, Dickson BM, Ong MS, Krajewski K, Houliston S, Kireev DB, Arrowsmith CH, Strahl BD (2013) Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. Genes Dev 27:1288–1298
Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269–277
Rush M, Appanah R, Lee S, Lam LL, Goyal P, Lorincz MC (2009) Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics 4:404–414
Sakai Y, Suetake I, Shinozaki F, Yamashina S, Tajima S (2004) Co-expression of de novo DNA methyltransferase Dnmt3a2 and Dnmt3L in gonocytes of mouse embryos. Gene Expr Patterns 5:231–237
Sakamoto Y, Watanabe S, Ichimura T, Kawasuji M, Koseki H, Baba H, Nakao M (2007) Overlapping roles of the methylated DNA-binding protein MBD1 and polycomb group proteins in transcriptional repression of HOXA genes and heterochromatin foci formation. J Biol Chem 282:16391–16400
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
Sato N, Kondo M, Arai K (2006) The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing. Biochem Biophys Res Commun 344:845–851
Schmitz KM, Mayer C, Postepska A, Grummt I (2010) Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev 24:2264–2269
Senyuk V, Premanand K, Xu P, Qian Z, Nucifora G (2011) The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA. PLoS One 6, e20793
Shamay M, Greenway M, Liao G, Ambinder RF, Hayward SD (2010) De novo DNA methyltransferase DNMT3b interacts with NEDD8-modified proteins. J Biol Chem 285:36377–36386
Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, Shinga J, Mizutani-Koseki Y, Okamura K, Tajima S, Mitsuya K, Okano M, Koseki H (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450:908–912
Shirane K, Toh H, Kobayashi H, Miura F, Chiba H, Ito T, Kono T, Sasaki H (2013) Mouse oocyte methylomes at base resolution reveal genome-wide accumulation of non-CpG methylation and role of DNA methyltransferases. PLoS Genet 9, e1003439
Smallwood A, Estève PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169–1178
Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335:709–712
Stroud H, Do T, Du J, Zhong X, Feng S, Johnson L, Patel DJ, Jacobsen SE (2014) Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis. Nat Struct Mol Biol 21:64–72
Suetake I, Kano Y, Tajima S (1998) Effect of aphidicolin on DNA methyltransferase in the nucleus. Cell Struct Funct 23:137–142
Suetake I, Miyazaki J, Murakami C, Takeshima H, Tajima S (2003) Distinct enzymatic properties of recombinant mouse DNA methyltransferases Dnmt3a and Dnmt3b. J Biochem 133:737–744
Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S (2004) DNMT3L stimulates DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem 279:27816–27823
Suetake I, Hayata D, Tajima S (2006a) The amino-terminus of mouse DNA methyltransferase 1 forms an independent domain and binds to DNA with the sequence involving PCNA binding motif. J Biochem 140:763–777
Suetake I, Morimoto Y, Fuchikami T, Abe K, Tajima S (2006b) Stimulation effect of Dnmt3L on the DNA methylation activity of Dnmt3a2. J Biochem 140:553–559
Sugiyama Y, Hatano N, Sueyoshi N, Suetake I, Tajima S, Kinoshita E, Kinoshita-Kikuta E, Koike T, Kameshita I (2010) The DNA-binding activity of mouse DNA methyltransferase 1 is regulated by phosphorylation with casein kinase 1δ/ε. Biochem J 427:489–497
Suzuki MM, Kerr AR, De Sousa D, Bird A (2007) CpG methylation is targeted to transcription units in an invertebrate genome. Genome Res 17:625–631
Takagi H, Tajima S, Asano A (1995) Overexpression of DNA methyltransferase in myoblast cells accelerates myotube formation. Eur J Biochem 231:282–291
Takeshima H, Suetake I, Shimahara H, Tate S, Ura K, Tajima S (2006) Distinct DNA methylation activity of DNA methyltransferases Dnmt3a and Dnmt3b towards the DNA in nucleosome. J Biochem 139:503–515
Takeshima H, Suetake I, Tajima S (2008) Mouse Dnmt3a preferentially methylates linker DNA, and is inhibited by histone H1. J Mol Biol 383:810–821
Takeshita K, Suetake I, Yamashita E, Suga M, Narita H, Nakagawa A, Tajima S (2011) Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Proc Natl Acad Sci USA 108:9055–9059
Tamaru H, Selker EU (2001) A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414:277–283
Umezawa A, Yamamoto H, Rhodes K, Klemsz MJ, Maki RA, Oshima RG (1997) Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression. Mol Cell Biol 17:4885–4894
Ushijima T, Watanabe N, Okochi E, Kaneda A, Sugimura T, Miyamoto K (2003) Fidelity of the methylation pattern and its variation in the genome. Genome Res 13:868–874
Van Emburgh BO, Robertson KD (2011) Modulation of Dnmt3b function in vitro by interactions with Dnmt3L, Dnmt3a and Dnmt3b splice variants. Nucleic Acids Res 39:4984–5002
Vertino PM, Yen RW, Gao J, Baylin SB (1996) De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Mol Cell Biol 16:4555–4565
Vilkaitis G, Suetake I, Klimasauskas S, Tajima S (2005) Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase. J Biol Chem 280:63–72
Wang YA, Kamarova Y, Shen KC, Jiang Z, Hahn MJ, Wang Y, Brooks SC (2005) DNA methyltransferase-3a interacts with p53 and represses p53-mediated gene expression. Cancer Biol Ther 4:1138–1143
Watanabe D, Suetake I, Tada T, Tajima S (2002) Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mech Dev 118:187–190
Watanabe D, Suetake I, Tajima S, Hanaoka K (2004) Expression of Dnmt3b in mouse hematopoietic progenitor cells and spermatogonia at specific stages. Gene Expr Patterns 5:43–49
Weisenberger DJ, Velicescu M, Preciado-Lopez MA, Gonzales FA, Tsai YC, Liang G, Jones PA (2002) Identification and characterization of alternatively spliced variants of DNA methyltransferase 3a in mammalian cells. Gene 298:91–99
Weisenberger DJ, Velicescu M, Cheng JC, Gonzales FA, Liang G, Jones PA (2004) Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. Mol Cancer Res 2:62–72
Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, Melberg A, Cornelio F, Urban AE, Pizza F, Poli F, Grubert F, Wieland T, Graf E, Hallmayer J, Strom TM, Mignot E (2012) Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 21:2205–2210
Xu G, Bestor TH, Bourc'his D, Hsieh C, 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
Yoder JA, Bestor TH (1998) A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7:279–284
Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340
Zemach A, Kim MY, Hsieh P, Coleman-Derr D, Eshed-Williams L, Thao K, Harmer SL, Zilberman D (2013) The Arabidopsis nucleosome remodeler DDM1 allows DNA methyltransferases to access H1-containing heterochromatin. Cell 153:193–205
Zhang G, Huang H, Liu D, Cheng Y, Liu X, Zhang W, Yin R, Zhang D, Zhang P, Liu J, Li C, Liu B, Luo Y, Zhu Y, Zhang N, He S, He C, Wang H, Chen D (2015) N6-methyladenine DNA modification in Drosophila. Cell 161:893–906
Zhang Y, Jurkowska R, Soeroes S, Rajavelu A, Dhayalan A, Bock I, Rathert P, Brandt O, Reinhardt R, Fischle W, Jeltsch A (2010) Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail. Nucleic Acids Res 38:4246–4253
Zhao X, Ueba T, Christie BR, Barkho B, McConnell MJ, Nakashima K, Lein ES, Eadie BD, Willhoite AR, Muotri AR, Summers RG, Chun J, Lee KF, Gage FH (2003) Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci USA 100:6777–6782
Zhao Q, Rank G, Tan YT, Li H, Moritz RL, Simpson RJ, Cerruti L, Curtis DJ, Patel DJ, Allis CD, Cunningham JM, Jane SM (2009) PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat Struct Mol Biol 16:304–311
Zhu B, Zheng Y, Angliker H, Schwarz S, Thiry S, Siegmann M, Jost JP (2000) 5-Methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. Nucleic Acids Res 28:4157–4165
Zhu H, Geiman TM, Xi S, Jiang Q, Schmidtmann A, Chen T, Li E, Muegge K (2006) Lsh is involved in de novo methylation of DNA. EMBO J 25:335–345
Zuo X, Sheng J, Lau HT, McDonald CM, Andrade M, Cullen DE, Bell FT, Iacovino M, Kyba M, Xu G, Li X (2012) Zinc finger protein ZFP57 requires its co-factor to recruit DNA methyltransferases and maintains DNA methylation imprint in embryonic stem cells via its transcriptional repression domain. J Biol Chem 287:2107–2118
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Tajima, S., Kimura, H., Suetake, I. (2016). Establishment and Maintenance of DNA Methylation. In: Hanaoka, F., Sugasawa, K. (eds) DNA Replication, Recombination, and Repair. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55873-6_20
Download citation
DOI: https://doi.org/10.1007/978-4-431-55873-6_20
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55871-2
Online ISBN: 978-4-431-55873-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)