A conserved function of EZH2-PRC2 in the repression of primitive endoderm cell fate [CUT&Tag]

In early blastocyst, inner cell mass (ICM) initiates the second wave of cell fate decisions to generate epiblast and primitive endoderm (PrE), crucial for proper embryo development. However, the epigenetic mechanisms underlying this segregation remain incompletely understood. Here, we reveal that treatment of embryonic stem cells (ESCs) with the EZH2 inhibitor EPZ-6438 significantly enhances transdifferentiation efficiency from ESCs to primitive endoderm stem cells (PrESCs). EZH2 knockout in ESCs markedly reduces H3K27me3 modification near the promoter regions of PrE-specific genes, upregulating their expression and promoting transition to PrESCs. Overexpression of wildtype EZH2, but not catalytic site or EED-binding motif mutants, prevents this transition. Notably, the ICM of mouse blastocysts treated with EPZ6438 at 8-cell stage contain almost no epiblast but only GATA6 positive cells. Finally, EPZ6438 treatment in human naïve ESCs upregulates hypoblast-associated genes. These findings demonstrated the conserved function of EZH2-PRC2 in protecting the pluripotency from primitive endoderm cell fate.