Reprogramming of H3K36me2 guides lineage- and locus-specific post-implantation DNA methylation [ChIP-Seq]

In mammals, DNA methylation is rapidly re-established after implantation following global erasure in pre-implantation embryos, the regulation of which, however, is not completely understood. Here, by mapping H3K36me2 in pre- and post-implantation mouse embryos, we unravel the dynamic reprogramming of H3K36me2 in mouse early development and its role in post-implantation de novo DNA methylation. Parental H3K36me2 was progressively lost by the 8-cell stage, while de novo H3K36me2 was established at putative enhancers after ZGA mediated by histone acetylation, followed by genome-wide deposition after implantation. H3K36me2 was however excluded from the inactive X chromosome. Catalytic mutation of NSD1, the major H3K36me2 methyltransferase, compromised post-implantation development and DNA methylation re-establishment, with extra-embryonic lineages more severely affected than embryonic lineages. De novo DNA methylation establishment in embryonic lineages partially bypassed H3K36me2/3 through elevated DNMT3B expression. Mechanistically, the PWWP domain of DNMT3A, but not that of DNMT3B, confers strict requirement of H3K36me2/3 for DNA methylation, while DNMT3B is a “leaky” reader of H3K36 methylation. Nevertheless, germline-specific genes, including those contain CpG islands at promoters, still require H3K36me2 to be efficiently methylated and silenced. Amid global remethylation, DNA methylation valleys (DMVs) escape de novo DNA methylation, where PRC1 and H2AK119ub1 antagonize H3K36me2 invasion. Thus, reprogramming of H3K36me2 is required for early embryogenesis and regulates lineage- and locus-specific post-implantation DNA methylation establishment.