Epigenomic study of early mammalian development

Histone modifications are fundamental epigenetic regulators that dictate stem cell potency. We surveyed the landscape of H3K4me3, a histone hallmark for transcription initiation, from developing gametes to post-implantation embryos using a highly sensitive approach, STAR ChIP-seq. Upon fertilization, extensive reprogramming occurs on the paternal genome, as H3K4me3 peaks are depleted in zygotes but are readily observed after major zygotic genome activation at the late two-cell stage. On the maternal genome, we found a non-canonical form of H3K4me3 (ncH3K4me3) in full-grown and mature oocytes, which exists as broad peaks at promoters and a large number of distal loci. Such broad H3K4me3 peaks are in contrast to the typical sharp H3K4me3 peaks of promoters. The ncH3K4me3 in oocytes then is inherited in zygotes and early 2-cell embryos, before being erased in the late 2-cell embryos, when canonical H3K4me3 starts to be established. Interestingly, downregulation of H3K4me3 in full-grown oocytes by overexpression of the H3K4me3 demethylase KDM5b lead to reactivation of transcription in GV oocytes.We also investigated chromatin landscape during human embryo preimplantation development, using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. There were both conservation and difference in developmentally significant transcription factor expression in human and mouse preimplantation embryos. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA), many reside in distal regions that are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of ncH3K4me3. Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization.