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

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Abstract
Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, but the extent of this reprogramming and its molecular mechanisms are poorly understood. Here, DNA methylation profiling in PGCs reveals a genome-wide erasure of methylation, with female PGCs being less methylated than male ones. A deficiency of the cytidine deaminase AID interferes with the genome-wide erasure of DNA methylation, suggesting that AID has a critical function in epigenetic reprogramming. The extent of epigenetic reprogramming in mammalian primordial germ cells (PGCs) and in early embryos, and its molecular mechanisms, are poorly understood. DNA methylation profiling in PGCs now reveals a genome–wide erasure of methylation, with female PGCs being less methylated than male ones. A deficiency of the cytidine deaminase AID interferes with the genome–wide erasure of DNA methylation, indicating that AID has a critical function in epigenetic reprogramming. 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 pluripotency1,2,3,4,5,6,7,8,9. 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 occurs10. Here we profiled DNA methylation throughout the genome by unbiased bisulphite next generation sequencing11,12,13 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.