Decoding the cell intrinsic and extrinsic roles of PRC2 in early embryogenesis.

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 protein degradation tag (dTAG) system, here we decode stage- and lineage-specific functions of Eed, a core component of Polycomb Repressive Complex 2 (PRC2) in mouse early embryogenesis. Our results reveal previously underappreciated cell intrinsic and extrinsic functions of PRC2 in regulating pre-implantation and primordial germ cell (PGC) development, respectively. We demonstrate that PRC2 is required for normal maternal to zygotic transition (MZT), and epiblast (EPI) specification. Moreover, PRC2 controls proper PGC numbers in EPI through a PRC2-ESRRB-BMP4 regulatory axis in extraembryonic ectoderm (ExE). Thus, our study uncovers a previously unknown cell-autonomous function of PRC2 in preimplantation development and its non-cell-autonomous function in PGC number regulation, both through interplays between epigenetic-epigenetic and epigenetic-TFs networks.