Decoding stage-specific functions of PRC2 uncovers a cell-autonomous role in preimplantation development and a non-cell-autonomous role in primordial germ cell fate

Abstract

Early embryogenesis is accompanied by dynamic epigenetic modifications. While such dynamics are important in cell intrinsic regulation of gene expression, their extrinsic roles in mediating intercellular communication during early embryogenesis is less understood. Using the dTAG system, here we reveal previously underappreciated stage-specific functions of PRC2 in regulating pre-implantation and primordial germ cell (PGC) development. We demonstrate that PRC2 plays important roles in regulating maternal to zygotic transition (MZT), and epiblast (EPI) formation. By systematically analyzing 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 EPI by controlling Esrrb expression in the extraembryonic ectoderm (ExE). 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-TFs networks.