The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [WGBS]

ABSTRACT: DNA methylation (DNAme) controls gene expression, genome stability and cell identity in many mammalian organisms. Genomes of most somatic cells and spermatozoa are largely methylated, apart from CpG-dense sequences including gene promoters1. In mouse oocytes, DNAme is mostly limited to transcribed regions2,3. The mechanisms restricting global DNAme acquisition in developing oocytes and the relevance thereof for regulating gene expression and embryo development after fertilization are unknown. Here we show that the histone H3 lysine 36 dimethyl (H3K36me2) demethylases KDM2A and KDM2B redundantly execute multiple chromatin functions during oocyte development, which are vital to pre- and post-implantation development. Firstly, by serving as recruitment factors of variant Polycomb Repressive Complex 1 (vPRC1), they control genome-wide H2A mono-ubiquitination deposition (H2AK119u1) and PRC1-dependent gene repression4. Secondly, as demethylases, KDM2A/KDM2B prevent global H3K36me2 accumulation, thereby impeding DNMT3A-catalyzed de novo DNAme within PRC1-controlled promoter, genic, and intergenic regions, and even at non-PRC1-controlled CpG-dense gene promoters5. Decisively, we demonstrate that aberrant Dnmt3a-dependent DNAme established in Kdm2a/Kdm2b double mutant oocytes represses transcription from maternal loci in two-cell embryos and impairs pre-implantation development. Hence, KDM2A/KDM2B are essential for defining the appropriate oocyte DNA methylome which in turn conveys 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. Lastly, our work shows that early development is vulnerable to gene dosage haplo-insufficiency effects, possibly in a parental-specific manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE234966 | GEO | 2025/03/27

REPOSITORIES: GEO