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Pathways of DNA Demethylation

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DNA Methyltransferases - Role and Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 945))

Abstract

The regulation of the genome relies on the epigenome to instruct, define and restrict the activities of growth and development. Among the cohort of epigenetic instructions, DNA methylation is perhaps the best understood. In most mammals, cycles of the addition and removal of DNA methylation constitute phases of reprogramming when the developing embryo must negotiate lineage defining and developmental commitment events. In these instances, the DNA methylation instruction is often removed, thereby allowing a change in permission for future development and a return to a more plastic and pluripotent state. Because of this, the germ line, upon demethylation, can give rise to gametes that are fully functional across generations and poised for totipotency. This return to a less differentiated state can also be achieved experimentally. The loss of DNA methylation constitutes one of the significant barriers to induced pluripotency and is a prerequisite for the generation of iPS cells. Taking fully differentiated cells, such as skin cells, and turning back the developmental clock heralded a technological breakthrough discovery in 2006 (Takahashi and Yamanaka 2006) with unprecedented promise in regenerative medicine. In this chapter, the mechanistic possibilities for DNA demethylation will be described in the context of natural and experimentally induced epigenetic reprogramming. The balance of the maintenance of this heritable mark together with its timely removal is essential for lifelong health and may be a key in our understanding of ageing.

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Abbreviations

5caC:

5-Carboxylcytosine

5fC:

5-Formylcytosine

5hmC:

5-Hydroxymethylcytosine

5mC:

5-Methylcytosine

A:

Adenosine

AID:

Activation-induced deaminase

AICDA:

Activation-induced cytosine deaminase

Ape1:

Apurinic/apyrimidinic (AP) endonuclease 1

APOBEC:

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like

BER:

Base excision repair

C:

Cytosine

CpA:

Cytosine–adenosine dinucleotide

CpG:

Cytosine–guanosine dinucleotide

CGI:

CpG islands

CXXC:

Zinc finger protein-binding domain to non-methylated CpG

CHH:

Asymmetric DNA methylation

DNA:

Deoxyribonucleic acid

ES cells:

Embryonic stem cells

DNMTs:

DNA methyltransferases, Dnmt1, DNA (cytosine-5)-methyltransferase 1; Dnmt1o, DNA (cytosine-5)-methyltransferase 1 oocyte form; Dnmt1s, DNA (cytosine-5)-methyltransferase 1 somatic form; Dnmt3a, DNA (cytosine-5)-methyltransferase 3a

Dnmt3b:

DNA (cytosine-5)-methyltransferase 3b

Dnmt3L:

DNA (cytosine-5)-methyltransferase 3-like, E6.5, embryonic day 6.5

E13.5:

Embryonic day thirteen

EGFP:

Enhanced green fluorescent protein

ELP1:

Elongator complex protein 1

ELP3:

Elongator complex protein 3

ELP4:

Elongator complex protein 4

GV:

Germinal vesicle

GVOs:

Germinal vesicle oocytes

GSE:

Gonad-specific expression

G:

Guanosine

IAP:

Intracisternal A particles, IF, immunofluorescence

iPS cells:

Induced pluripotent stem cells

H3K9me2:

Histone H3 lysine 9 dimethylation

KO:

Knockout, MBD2, methyl-CpG-binding domain 2

MBD4:

Methyl-CpG-binding domain 4

NGS:

Next-generation sequencing

NER:

Nucleotide excision repair

Np95:

Nuclear protein 95

RFTD:

Replication foci targeting domain

PARP1:

Poly-ADP-ribose polymerase 1

PRC2:

Polycomb repressive complex

PGCs:

Primordial germ cells

RRBS:

Reduced representational bisulphite sequencing

RNA:

Ribonucleic acid

RNAi:

RNA interference

SAM:

S-Adenosyl-L-methionine

siRNA:

Small interfering RNA

SMUG1:

Single-strand selective monofunctional uracil DNA glycosylase 1

SNT:

Somatic nuclear transfer

T:

Thymine

TDG:

Thymine DNA glycosylase

TET1–3:

Ten-eleven translocation 1, 2 or 3

U:

Uracil

UNG2, ZGA:

Zygotic genome activation

References

  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. DNA repair. In: Molecular biology of the cell. 4th ed. New York: Garland Science; 2002.

    Google Scholar 

  • Amouroux R, Nashun B, Shirane K, Nakagawa S, Hill PW, D’Souza Z, Nakayama M, Matsuda M, Turp A, Ndjetehe E, Encheva V, Kudo NR, Koseki H, Sasaki H, Hajkova P. De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat Cell Biol. 2016;18(2):225–33. doi:10.1038/ncb3296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnetova I, Fulka H, Fulka Jr J. Epigenetic characteristics of paternal chromatin in interspecies zygotes. J Reprod Dev. 2010;56(6):601–6.

    Article  PubMed  Google Scholar 

  • Beaujean N, Taylor JE, McGarry M, Gardner JO, Wilmut I, Loi P, Ptak G, Galli C, Lazzari G, Bird A, Young LE, Meehan RR. The effect of interspecific oocytes on demethylation of sperm DNA. Proc Natl Acad Sci U S A. 2004;101(20):7636–40. doi:10.1073/pnas.0400730101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bestor TH. The host defence function of genomic methylation patterns. Novartis Found Symp. 1998;214:187–95; discussion 195–189, 228–132.

    CAS  PubMed  Google Scholar 

  • Bhattacharya SK, Ramchandani S, Cervoni N, Szyf M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature. 1999;397(6720):579–83. doi:10.1038/17533.

    Article  CAS  PubMed  Google Scholar 

  • Bird AP. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 1980;8(7):1499–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S, Tam A, Laird DJ, Hirst M, Rao A, Lorincz MC, Ramalho-Santos M. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature. 2013;500(7461):222–6. doi:10.1038/nature12362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boeke J, Ammerpohl O, Kegel S, Moehren U, Renkawitz R. The minimal repression domain of MBD2b overlaps with the methyl-CpG-binding domain and binds directly to Sin3A. J Biol Chem. 2000;275(45):34963–7. doi:10.1074/jbc.M005929200.

    Article  CAS  PubMed  Google Scholar 

  • Bouniol-Baly C, Hamraoui L, Guibert J, Beaujean N, Szollosi MS, Debey P. Differential transcriptional activity associated with chromatin configuration in fully grown mouse germinal vesicle oocytes. Biol Reprod. 1999;60(3):580–7.

    Article  CAS  PubMed  Google Scholar 

  • Bourc’his D, Le Bourhis D, Patin D, Niveleau A, Comizzoli P, Renard JP, Viegas-Pequignot E. Delayed and incomplete reprogramming of chromosome methylation patterns in bovine cloned embryos. Curr Biol. 2001;11(19):1542–6.

    Article  PubMed  Google Scholar 

  • Braun RE. Packaging paternal chromosomes with protamine. Nat Genet. 2001;28(1):10–2. doi:10.1038/88194.

    CAS  PubMed  Google Scholar 

  • Brewer LR, Corzett M, Balhorn R. Protamine-induced condensation and decondensation of the same DNA molecule. Science. 1999;286(5437):120–3.

    Article  CAS  PubMed  Google Scholar 

  • Broderick JB, Duffus BR, Duschene KS, Shepard EM. Radical S-adenosylmethionine enzymes. Chem Rev. 2014;114(8):4229–317. doi:10.1021/cr4004709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cardoso MC, Leonhardt H. DNA methyltransferase is actively retained in the cytoplasm during early development. J Cell Biol. 1999;147(1):25–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlson LL, Page AW, Bestor TH. Properties and localization of DNA methyltransferase in preimplantation mouse embryos: implications for genomic imprinting. Genes Dev. 1992;6(12B):2536–41.

    Article  CAS  PubMed  Google Scholar 

  • Cedar H, Solage A, Glaser G, Razin A. Direct detection of methylated cytosine in DNA by use of the restriction enzyme MspI. Nucleic Acids Res. 1979;6(6):2125–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng X, Roberts RJ, AdoMet-dependent methylation, DNA methyltransferases and base flipping. Nucleic Acids Res. 2001;29:3784–95.

    Google Scholar 

  • Chen T, Ueda Y, Dodge JE, Wang Z, Li E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol. 2003;23(16):5594–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Guo L, Zhang L, Wu H, Yang J, Liu H, Wang X, Hu X, Gu T, Zhou Z, Liu J, Liu J, Wu H, Mao SQ, Mo K, Li Y, Lai K, Qi J, Yao H, Pan G, Xu GL, Pei D. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet. 2013;45(12):1504–9. doi:10.1038/ng.2807.

    Article  CAS  PubMed  Google Scholar 

  • Chiu YL, Greene WC. The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu Rev Immunol. 2008;26:317–53. doi:10.1146/annurev.immunol.26.021607.090350.

    Article  CAS  PubMed  Google Scholar 

  • Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 1994;22(15):2990–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Constantinides PG, Jones PA, Gevers W. Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature. 1977;267(5609):364–6.

    Article  CAS  PubMed  Google Scholar 

  • Conticello SG, Thomas CJ, Petersen-Mahrt SK, Neuberger MS. Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. Mol Biol Evol. 2005;22(2):367–77. doi:10.1093/molbev/msi026.

    Article  CAS  PubMed  Google Scholar 

  • Dean W. DNA methylation and demethylation: a pathway to gametogenesis and development. Mol Reprod Dev. 2014;81(2):113–25. doi:10.1002/mrd.22280.

    Article  CAS  PubMed  Google Scholar 

  • Dean W, Santos F, Stojkovic M, Zakhartchenko V, Walter J, Wolf E, Reik W. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc Natl Acad Sci U S A. 2001;98(24):13734–8. doi:10.1073/pnas.241522698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derijck AA, van der Heijden GW, Giele M, Philippens ME, van Bavel CC, de Boer P. gammaH2AX signalling during sperm chromatin remodelling in the mouse zygote. DNA Repair (Amst). 2006;5(8):959–71. doi:10.1016/j.dnarep.2006.05.043.

    Article  CAS  Google Scholar 

  • Derijck A, van der Heijden G, Giele M, Philippens M, de Boer P. DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation. Hum Mol Genet. 2008;17(13):1922–37. doi:10.1093/hmg/ddn090.

    Article  CAS  PubMed  Google Scholar 

  • Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, Gehrke C. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 1982;10(8):2709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89–92.

    Article  CAS  PubMed  Google Scholar 

  • Ficz G, Hore TA, Santos F, Lee HJ, Dean W, Arand J, Krueger F, Oxley D, Paul YL, Walter J, Cook SJ, Andrews S, Branco MR, Reik W. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell. 2013;13(3):351–9. doi:10.1016/j.stem.2013.06.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franchini DM, Chan CF, Morgan H, Incorvaia E, Rangam G, Dean W, Santos F, Reik W, Petersen-Mahrt SK. Processive DNA demethylation via DNA deaminase-induced lesion resolution. PLoS One. 2014;9(7):e97754. doi:10.1371/journal.pone.0097754.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A. 1992;89(5):1827–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983;11(19):6883–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grippo P, Iaccarino M, Parisi E, Scarano E. Methylation of DNA in developing sea urchin embryos. J Mol Biol. 1968;36(2):195–208.

    Article  CAS  PubMed  Google Scholar 

  • Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabo PE, Pfeifer GP, Li J, Xu GL. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011;477(7366):606–10. doi:10.1038/nature10443.

    Article  CAS  PubMed  Google Scholar 

  • Guenatri M, Bailly D, Maison C, Almouzni G. Mouse centric and pericentric satellite repeats form distinct functional heterochromatin. J Cell Biol. 2004;166(4):493–505. doi:10.1083/jcb.200403109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guibert S, Forne T, Weber M. Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res. 2012;22(4):633–41. doi:10.1101/gr.130997.111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo F, Li X, Liang D, Li T, Zhu P, Guo H, Wu X, Wen L, Gu TP, Hu B, Walsh CP, Li J, Tang F, Xu GL. Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell. 2014;15(4):447–58. doi:10.1016/j.stem.2014.08.003.

    Article  CAS  PubMed  Google Scholar 

  • Hackett JA, Zylicz JJ, Surani MA. Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet. 2012;28(4):164–74. doi:10.1016/j.tig.2012.01.005.

    Article  CAS  PubMed  Google Scholar 

  • Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science. 2013;339(6118):448–52. doi:10.1126/science.1229277.

    Article  CAS  PubMed  Google Scholar 

  • Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA. Epigenetic reprogramming in mouse primordial germ cells. Mech Dev. 2002;117(1–2):15–23.

    Article  CAS  PubMed  Google Scholar 

  • Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science. 2010;329(5987):78–82. doi:10.1126/science.1187945.

    Article  CAS  PubMed  Google Scholar 

  • Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995;55(20):4525–30.

    CAS  PubMed  Google Scholar 

  • Hirasawa R, Sasaki H. Dynamic transition of Dnmt3b expression in mouse pre- and early post-implantation embryos. Gene Expr Patterns. 2009;9(1):27–30. doi:10.1016/j.gep.2008.09.002.

    Article  CAS  PubMed  Google Scholar 

  • Hotchkiss RD. The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem. 1948;175(1):315–32.

    CAS  PubMed  Google Scholar 

  • Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Chaillet JR. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell. 2001;104(6):829–38.

    Article  CAS  PubMed  Google Scholar 

  • Howlett SK, Reik W. Methylation levels of maternal and paternal genomes during preimplantation development. Development. 1991;113(1):119–27.

    CAS  PubMed  Google Scholar 

  • Ichiyanagi K, Li Y, Watanabe T, Ichiyanagi T, Fukuda K, Kitayama J, Yamamoto Y, Kuramochi-Miyagawa S, Nakano T, Yabuta Y, Seki Y, Saitou M, Sasaki H. Locus- and domain-dependent control of DNA methylation at mouse B1 retrotransposons during male germ cell development. Genome Res. 2011;21(12):2058–66. doi:10.1101/gr.123679.111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue A, Zhang Y. Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science. 2011;334(6053):194. doi:10.1126/science.1212483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue A, Shen L, Dai Q, He C, Zhang Y. Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res. 2011;21(12):1670–6. doi:10.1038/cr.2011.189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue A, Shen L, Matoba S, Zhang Y. Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts. Cell Rep. 2015;10(4):463–70. doi:10.1016/j.celrep.2014.12.049.

    Article  CAS  PubMed  Google Scholar 

  • Iqbal K, Jin SG, Pfeifer GP, Szabo PE. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A. 2011;108(9):3642–7. doi:10.1073/pnas.1014033108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. doi:10.1038/nature09303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54. doi:10.1038/ng1089.

    Article  CAS  PubMed  Google Scholar 

  • Kaneda M, Hirasawa R, Chiba H, Okano M, Li E, Sasaki H. Genetic evidence for Dnmt3a-dependent imprinting during oocyte growth obtained by conditional knockout with Zp3-Cre and complete exclusion of Dnmt3b by chimera formation. Genes Cells. 2010;15(3):169–79. doi:10.1111/j.1365-2443.2009.01374.x.

    Article  CAS  PubMed  Google Scholar 

  • Kangaspeska S, Stride B, Metivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP, Benes V, Gannon F, Reid G. Transient cyclical methylation of promoter DNA. Nature. 2008;452(7183):112–5. doi:10.1038/nature06640.

    Article  CAS  PubMed  Google Scholar 

  • Kishigami S, Van Thuan N, Hikichi T, Ohta H, Wakayama S, Mizutani E, Wakayama T. Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids. Dev Biol. 2006;289(1):195–205. doi:10.1016/j.ydbio.2005.10.026.

    Article  CAS  PubMed  Google Scholar 

  • Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–43. doi:10.1038/nature09586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi H, Sakurai T, Imai M, Takahashi N, Fukuda A, Yayoi O, Sato S, Nakabayashi K, Hata K, Sotomaru Y, Suzuki Y, Kono T. Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks. PLoS Genet. 2012;8(1):e1002440. doi:10.1371/journal.pgen.1002440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kothari RM, Shankar V. 5-Methylcytosine content in the vertebrate deoxyribonucleic acids: species specificity. J Mol Evol. 1976;7(4):325–9.

    Article  CAS  PubMed  Google Scholar 

  • Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324(5929):929–30. doi:10.1126/science.1169786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurimoto K, Yabuta Y, Ohinata Y, Shigeta M, Yamanaka K, Saitou M. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev. 2008;22(12):1617–35. doi:10.1101/gad.1649908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lane N, Dean W, Erhardt S, Hajkova P, Surani A, Walter J, Reik W. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis. 2003;35(2):88–93. doi:10.1002/gene.10168.

    Article  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. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol. 2003;13(14):1192–200.

    Article  CAS  PubMed  Google Scholar 

  • Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A, Surani MA, Hajkova P. Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol. 2013;20(3):311–6. doi:10.1038/nsmb.2510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462(7271):315–22. doi:10.1038/nature08514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longerich S, Basu U, Alt F, Storb U. AID in somatic hypermutation and class switch recombination. Curr Opin Immunol. 2006;18(2):164–74. doi:10.1016/j.coi.2006.01.008.

    Article  CAS  PubMed  Google Scholar 

  • Lucifero D, La Salle S, Bourc’his D, Martel J, Bestor TH, Trasler JM. Coordinate regulation of DNA methyltransferase expression during oogenesis. BMC Dev Biol. 2007;7:36. doi:10.1186/1471-213X-7-36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maatouk DM, Kellam LD, Mann MR, Lei H, Li E, Bartolomei MS, Resnick JL. DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development. 2006;133(17):3411–8. doi:10.1242/dev.02500.

    Article  CAS  PubMed  Google Scholar 

  • Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome. Nature. 2000;403(6769):501–2. doi:10.1038/35000654.

    Article  CAS  PubMed  Google Scholar 

  • McLay DW, Clarke HJ. Remodelling the paternal chromatin at fertilization in mammals. Reproduction. 2003;125(5):625–33.

    Article  CAS  PubMed  Google Scholar 

  • Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G. Cyclical DNA methylation of a transcriptionally active promoter. Nature. 2008;452(7183):45–50. doi:10.1038/nature06544.

    Article  CAS  PubMed  Google Scholar 

  • Monk M, Boubelik M, Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development. 1987;99(3):371–82.

    CAS  PubMed  Google Scholar 

  • Nabel CS, Jia H, Ye Y, Shen L, Goldschmidt HL, Stivers JT, Zhang Y, Kohli RM. AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat Chem Biol. 2012;8(9):751–8. doi:10.1038/nchembio.1042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H, Sekimoto T, Ikawa M, Yoneda Y, Okabe M, Tanaka S, Shiota K, Nakano T. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol. 2007;9(1):64–71. doi:10.1038/ncb1519.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Liu YJ, Nakashima H, Umehara H, Inoue K, Matoba S, Tachibana M, Ogura A, Shinkai Y, Nakano T. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature. 2012;486(7403):415–9. doi:10.1038/nature11093.

    CAS  PubMed  Google Scholar 

  • Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999;23(1):58–61. doi:10.1038/12659.

    Article  CAS  PubMed  Google Scholar 

  • Ohno R, Nakayama M, Naruse C, Okashita N, Takano O, Tachibana M, Asano M, Saitou M, Seki Y. A replication-dependent passive mechanism modulates DNA demethylation in mouse primordial germ cells. Development. 2013;140(14):2892–903. doi:10.1242/dev.093229.

    Article  CAS  PubMed  Google Scholar 

  • Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y. A role for the elongator complex in zygotic paternal genome demethylation. Nature. 2010;463(7280):554–8. doi:10.1038/nature08732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okae H, Chiba H, Hiura H, Hamada H, Sato A, Utsunomiya T, Kikuchi H, Yoshida H, Tanaka A, Suyama M, Arima T. Genome-wide analysis of DNA methylation dynamics during early human development. PLoS Genet. 2014;10(12):e1004868. doi:10.1371/journal.pgen.1004868.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Okamoto Y, Yoshida N, Suzuki T, Shimozawa N, Asami M, Matsuda T, Kojima N, Perry AC, Takada T. DNA methylation dynamics in mouse preimplantation embryos revealed by mass spectrometry. Sci Rep. 2016;6:19134. doi:10.1038/srep19134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oswald J, Engemann S, Lane N, Mayer W, Olek A, Fundele R, Dean W, Reik W, Walter J. Active demethylation of the paternal genome in the mouse zygote. Curr Biol. 2000;10(8):475–8.

    Article  CAS  PubMed  Google Scholar 

  • Peat JR, Dean W, Clark SJ, Krueger F, Smallwood SA, Ficz G, Kim JK, Marioni JC, Hore TA, Reik W. Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation. Cell Rep. 2014;9(6):1990–2000. doi:10.1016/j.celrep.2014.11.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaffeneder T, Spada F, Wagner M, Brandmayr C, Laube SK, Eisen D, Truss M, Steinbacher J, Hackner B, Kotljarova O, Schuermann D, Michalakis S, Kosmatchev O, Schiesser S, Steigenberger B, Raddaoui N, Kashiwazaki G, Muller U, Spruijt CG, Vermeulen M, Leonhardt H, Schar P, Muller M, Carell T. Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat Chem Biol. 2014;10(7):574–81. doi:10.1038/nchembio.1532.

    Article  CAS  PubMed  Google Scholar 

  • Polanski Z, Motosugi N, Tsurumi C, Hiiragi T, Hoffmann S. Hypomethylation of paternal DNA in the late mouse zygote is not essential for development. Int J Dev Biol. 2008;52(2–3):295–8. doi:10.1387/ijdb.072347zp.

    Article  PubMed  Google Scholar 

  • Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, Jacobsen SE, Reik W. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2010;463(7284):1101–5. doi:10.1038/nature08829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Probst AV, Santos F, Reik W, Almouzni G, Dean W. Structural differences in centromeric heterochromatin are spatially reconciled on fertilisation in the mouse zygote. Chromosoma. 2007;116(4):403–15. doi:10.1007/s00412-007-0106-8.

    Article  PubMed  Google Scholar 

  • Ratnam S, Mertineit C, Ding F, Howell CY, Clarke HJ, Bestor TH, Chaillet JR, Trasler JM. Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development. Dev Biol. 2002;245(2):304–14. doi:10.1006/dbio.2002.0628.

    Article  CAS  PubMed  Google Scholar 

  • Razin A, Webb C, Szyf M, Yisraeli J, Rosenthal A, Naveh-Many T, Sciaky-Gallili N, Cedar H. Variations in DNA methylation during mouse cell differentiation in vivo and in vitro. Proc Natl Acad Sci U S A. 1984;81(8):2275–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293(5532):1089–93. doi:10.1126/science.1063443.

    Article  CAS  PubMed  Google Scholar 

  • Riggs AD, Jones PA. 5-methylcytosine, gene regulation, and cancer. Adv Cancer Res. 1983;40:1–30.

    Article  CAS  PubMed  Google Scholar 

  • Rougier N, Bourc’his D, Gomes DM, Niveleau A, Plachot M, Paldi A, Viegas-Pequignot E. Chromosome methylation patterns during mammalian preimplantation development. Genes Dev. 1998;12(14):2108–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Russell GJ, Walker PM, Elton RA, Subak-Sharpe JH. Doublet frequency analysis of fractionated vertebrate nuclear DNA. J Mol Biol. 1976;108(1):1–23.

    Article  CAS  PubMed  Google Scholar 

  • Saksouk N, Barth TK, Ziegler-Birling C, Olova N, Nowak A, Rey E, Mateos-Langerak J, Urbach S, Reik W, Torres-Padilla ME, Imhof A, Dejardin J, Simboeck E. Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation. Mol Cell. 2014;56(4):580–94. doi:10.1016/j.molcel.2014.10.001.

    Article  CAS  PubMed  Google Scholar 

  • Sanford J, Forrester L, Chapman V, Chandley A, Hastie N. Methylation patterns of repetitive DNA sequences in germ cells of Mus musculus. Nucleic Acids Res. 1984;12(6):2823–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santos F, Hendrich B, Reik W, Dean W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol. 2002;241(1):172–82. doi:10.1006/dbio.2001.0501.

    Article  CAS  PubMed  Google Scholar 

  • Santos F, Peters AH, Otte AP, Reik W, Dean W. Dynamic chromatin modifications characterise the first cell cycle in mouse embryos. Dev Biol. 2005;280(1):225–36. doi:10.1016/j.ydbio.2005.01.025.

    Article  CAS  PubMed  Google Scholar 

  • Santos F, Peat J, Burgess H, Rada C, Reik W, Dean W. Active demethylation in mouse zygotes involves cytosine deamination and base excision repair. Epigenetics Chromatin. 2013;6(1):39. doi:10.1186/1756-8935-6-39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, Popp C, Thienpont B, Dean W, Reik W. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell. 2012;48(6):849–62. doi:10.1016/j.molcel.2012.11.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seki Y, Hayashi K, Itoh K, Mizugaki M, Saitou M, Matsui Y. Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev Biol. 2005;278(2):440–58. doi:10.1016/j.ydbio.2004.11.025.

    Article  CAS  PubMed  Google Scholar 

  • Seki Y, Yamaji M, Yabuta Y, Sano M, Shigeta M, Matsui Y, Saga Y, Tachibana M, Shinkai Y, Saitou M. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development. 2007;134(14):2627–38. doi:10.1242/dev.005611.

    Article  CAS  PubMed  Google Scholar 

  • Shirane K, Toh H, Kobayashi H, Miura F, Chiba H, Ito T, Kono T, Sasaki H. Mouse oocyte methylomes at base resolution reveal genome-wide accumulation of non-CpG methylation and role of DNA methyltransferases. PLoS Genet. 2013;9(4):e1003439. doi:10.1371/journal.pgen.1003439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smallwood SA, Tomizawa S, Krueger F, Ruf N, Carli N, Segonds-Pichon A, Sato S, Hata K, Andrews SR, Kelsey G. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet. 2011;43(8):811–4. doi:10.1038/ng.864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith ZD, Chan MM, Mikkelsen TS, Gu H, Gnirke A, Regev A, Meissner A. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012;484(7394):339–44. doi:10.1038/nature10960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo PE, Pfeifer GP. H3K9me2 attracts PGC7 in the zygote to prevent Tet3-mediated oxidation of 5-methylcytosine. J Mol Cell Biol. 2012;4(6):427–9. doi:10.1093/jmcb/mjs038.

    Article  CAS  PubMed  Google Scholar 

  • Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5. doi:10.1126/science.1170116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi:10.1016/j.cell.2006.07.024.

    Article  CAS  PubMed  Google Scholar 

  • Tomizawa S, Kobayashi H, Watanabe T, Andrews S, Hata K, Kelsey G, Sasaki H. Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes. Development. 2011;138(5):811–20. doi:10.1242/dev.061416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsukada Y, Akiyama T, Nakayama KI. Maternal TET3 is dispensable for embryonic development but is required for neonatal growth. Sci Rep. 2015;5:15876. doi:10.1038/srep15876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Heijden GW, Dieker JW, Derijck AA, Muller S, Berden JH, Braat DD, van der Vlag J, de Boer P. Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote. Mech Dev. 2005;122(9):1008–22. doi:10.1016/j.mod.2005.04.009.

    Article  PubMed  CAS  Google Scholar 

  • Vincent JJ, Huang Y, Chen PY, Feng S, Calvopina JH, Nee K, Lee SA, Le T, Yoon AJ, Faull K, Fan G, Rao A, Jacobsen SE, Pellegrini M, Clark AT. Stage-specific roles for tet1 and tet2 in DNA demethylation in primordial germ cells. Cell Stem Cell. 2013;12(4):470–8. doi:10.1016/j.stem.2013.01.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet. 1999;23(1):62–6. doi:10.1038/12664.

    Article  CAS  PubMed  Google Scholar 

  • Wossidlo M, Arand J, Sebastiano V, Lepikhov K, Boiani M, Reinhardt R, Scholer H, Walter J. Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes. EMBO J. 2010;29(11):1877–88. doi:10.1038/emboj.2010.80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun. 2011;2:241. doi:10.1038/ncomms1240.

    Article  PubMed  CAS  Google Scholar 

  • Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 2014;156(1–2):45–68. doi:10.1016/j.cell.2013.12.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xue JH, Xu GF, Gu TP, Chen GD, Han BB, Xu ZM, Bjoras M, Krokan HE, Xu GL, Du YR. Uracil-DNA Glycosylase UNG Promotes Tet-mediated DNA Demethylation. J Biol Chem. 2016;291(2):731–8. doi:10.1074/jbc.M115.693861.

    Article  CAS  PubMed  Google Scholar 

  • Yamaji M, Ueda J, Hayashi K, Ohta H, Yabuta Y, Kurimoto K, Nakato R, Yamada Y, Shirahige K, Saitou M. PRDM14 ensures naive pluripotency through dual regulation of signaling and epigenetic pathways in mouse embryonic stem cells. Cell Stem Cell. 2013;12(3):368–82. doi:10.1016/j.stem.2012.12.012.

    Article  CAS  PubMed  Google Scholar 

  • Young LE, Beaujean N. DNA methylation in the preimplantation embryo: the differing stories of the mouse and sheep. Anim Reprod Sci. 2004;82–83:61–78. doi:10.1016/j.anireprosci.2004.05.020.

    Article  PubMed  CAS  Google Scholar 

  • Zheng P, Schramm RD, Latham KE. Developmental regulation and in vitro culture effects on expression of DNA repair and cell cycle checkpoint control genes in rhesus monkey oocytes and embryos. Biol Reprod. 2005;72(6):1359–69. doi:10.1095/biolreprod.104.039073.

    Article  CAS  PubMed  Google Scholar 

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  1. Epigenetics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK

    Wendy Dean

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  1. Institut für Biochemie, Universität Stuttgart, Stuttgart, Germany

    Albert Jeltsch

  2. BioMed X Innovation Center, Heidelberg, Germany

    Renata Z. Jurkowska

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Dean, W. (2016). Pathways of DNA Demethylation. In: Jeltsch, A., Jurkowska, R. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 945. Springer, Cham. https://doi.org/10.1007/978-3-319-43624-1_11

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