Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine

Science. 2013 Jan 25;339(6118):448-52. doi: 10.1126/science.1229277. Epub 2012 Dec 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism
  • Animals
  • CpG Islands
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA Methylation*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Embryo, Mammalian / metabolism*
  • Embryonic Development
  • Epigenesis, Genetic*
  • Female
  • Genomic Imprinting*
  • Germ Cells / metabolism*
  • Germ Layers / cytology
  • Male
  • Mice
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA-Binding Proteins / genetics

Substances

  • DAZL protein, mouse
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins
  • TET1 protein, mouse
  • Tet2 protein, mouse
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine