PRDM14 Ensures Naïve Pluripotency through Dual Regulation of Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells

Mouse embryonic stem cells (mESCs) fluctuate between a naïve inner cell mass (ICM)-like state and a primed epiblast-like state of pluripotency in serum, but are harnessed exclusively in a distinctive, naïve state of pluripotency that more faithfully captures the ICM state (the ground state) with inhibitors for mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i). Understanding the mechanism ensuring the naïve states of pluripotency will be critical to realizing the full potential of ESCs. We show here that PRDM14, a PR domain-containing transcriptional regulator, ensures naïve pluripotency by a dual mechanism: Antagonizing fibroblast growth factor receptor (FGFR) signaling that is activated paradoxically by the core transcriptional circuitry for pluripotency and directs a primed state, and repressing de novo DNA methyltransferases that create a primed epiblast-like epigenome. PRDM14 exerts these functions by recruiting polycomb repressive complex 2 (PRC2) specifically to key targets and repressing their expression.