Preventing CpG island hypermethylation in oocytes safeguards mouse development

Abstract

SUMMARYIn mammalian somatic and male germline cells, genomes are extensively DNA methylated (DNAme). In oocytes, however, DNAme is largely limited to transcribed regions only. Regulatory CpG-island (CGI) sequences are also devoid of repressive DNAme in somatic and germ cells of both sexes. The mechanisms restrictingde novoDNAme acquisition in developing oocytes, at CGIs and globally, and the relevance thereof for regulating zygotic gene expression and embryo development after fertilization are largely unknown. Here we show that the histone H3 lysine 36 dimethyl (H3K36me2) demethylases KDM2A and KDM2B prevent genome-wide accumulation of H3K36me2, thereby impeding global DNMT3A-catalyzedde novoDNAme, including at CGI gene promoters. By recruiting variant Polycomb Repressive Complex 1 (vPRC1), they further control H2A mono-ubiquitin deposition and vPRC1-dependent gene repression. Through genetic perturbations, we demonstrate that aberrantDnmt3a-dependent DNAme established inKdm2a/Kdm2bdouble mutant oocytes represses transcription from maternal loci in two-cell embryos. The lethality ofKdm2a/Kdm2bmaternally deficient pre-implantation embryos is suppressed byDnmt3adeficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte DNA methylome, conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient to erase aberrant DNAme from maternal chromatin, and that early development is vulnerable to gene dosage haplo-insufficiency effects.HIGHLIGHTSDemethylation of H3K36me2 by KDM2A and KDM2B prevents aberrant de novo DNA methylation in mouse oocytes.Sequence composition and H3K4me3 modulate the probability for aberrant H3K36me2 and DNA methylation at CpG islands.Aberrant oocyte DNA methylation is not reprogrammed in early embryos and suppresses maternal gene transcription.Aberrant oocyte DNA methylation causes embryonic lethality during pre-implantation development.GRAPHICAL SUMMARY