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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.

SUBMITTER: Hackett JA

PROVIDER: S-EPMC3847602 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine.

Hackett Jamie A JA Sengupta Roopsha R Zylicz Jan J JJ Murakami Kazuhiro K Lee Caroline C Down Thomas A TA Surani M Azim MA

Science (New York, N.Y.) 20121206 6118

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 f ...[more]

PMID: 23223451

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