title: Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine.
abstract: Mouse primordial germ cells (PGCs) undergo sequential epigenetic changes and genome-wide DNA demethylation to reset the epigenome for totipotency. Here, we demonstrate that erasure of CpG methylation (5mC) in PGCs occurs via conversion to 5-hydroxymethylcytosine (5hmC), driven by high levels of TET1 and TET2. Global conversion to 5hmC initiates asynchronously among PGCs at embryonic day (E) 9.5 to E10.5 and accounts for the unique process of imprint erasure. Mechanistically, 5hmC enrichment is followed by its protracted decline thereafter at a rate consistent with replication-coupled dilution. The conversion to 5hmC is an important component of parallel redundant systems that drive comprehensive reprogramming in PGCs. Nonetheless, we identify rare regulatory elements that escape systematic DNA demethylation in PGCs, providing a potential mechanistic basis for transgenerational epigenetic inheritance.
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Hackett
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
authors.forename: Roopsha
authors.initials: R
authors.lastname: Sengupta
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.|Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Zylicz
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lee
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Down
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.|Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: M Azim
authors.initials: MA
authors.lastname: Surani
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D004622:Embryo, Mammalian / Q000378:metabolism*; D047108:Embryonic Development; D044127:Epigenesis, Genetic; D005260:Female; D018392:Genomic Imprinting; D005854:Germ Cells / Q000378:metabolism*; D005855:Germ Layers / Q000166:cytology; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: C508515:DAZL protein, mouse; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse