Decoding stage-specific functions of PRC2 in early embryogenesis uncovers roles in preimplantation development and...

Early embryogenesis is accompanied by dynamic epigenetic modifications. Although such dynamics are important in cell intrinsic regulation of gene expression, their extrinsic roles in mediating intercellular communication during early embryogenesis are less understood. Here, using the dTAG system, we reveal previously underappreciated stage-specific functions of PRC2 in regulating preimplantation and primordial germ cell (PGC) development. We demonstrate that PRC2 plays important roles in regulating maternal-to-zygotic transition and epiblast formation. By systematically analysing H3K27me3 and H3K4me3 dynamics, we redefine the timing of bivalency establishment and uncover a stepwise mechanism governing bivalency acquisition in early embryogenesis. Moreover, PRC2 regulates proper PGC numbers in the epiblast by controlling Esrrb expression in the extraembryonic ectoderm. Thus, our study uncovers a previously unknown cell-autonomous function of PRC2 in preimplantation development and its non-cell-autonomous impact in PGC number regulation, both through interplays between epigenetic-epigenetic and epigenetic-transcription factors networks.