Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency

Nature. 2010 Feb 25;463(7284):1101-5. doi: 10.1038/nature08829.

Abstract

Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases AID and APOBEC1 can deaminate 5-methylcytosine in vitro and in Escherichia coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulphite next generation sequencing in wild-type and AID-deficient mouse PGCs at embryonic day (E)13.5. Wild-type PGCs revealed marked genome-wide erasure of methylation to a level below that of methylation deficient (Np95(-/-), also called Uhrf1(-/-)) embryonic stem cells, with female PGCs being less methylated than male ones. By contrast, AID-deficient PGCs were up to three times more methylated than wild-type ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in AID-deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. AID deficiency interferes with genome-wide erasure of DNA methylation patterns, indicating that AID has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins
  • Cytidine Deaminase / deficiency*
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • DNA Methylation*
  • DNA Transposable Elements / genetics
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / metabolism
  • Epigenesis, Genetic / genetics
  • Exons / genetics
  • Female
  • Genome* / genetics
  • Germ Cells / enzymology
  • Germ Cells / metabolism*
  • Introns / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Octamer Transcription Factor-3 / genetics
  • Ubiquitin-Protein Ligases

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA Transposable Elements
  • Nuclear Proteins
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Uhrf1 protein, mouse
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase

Associated data

  • GEO/GSE19960