PRDM14 Ensures a Nave Pluripotency by a Dual Mechanism Involving Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells

Mouse embryonic stem cells (mESCs) fluctuate between a nave inner cell mass (ICM)-like state and a primed epiblast-like state of pluripotency in serum, but are harnessed exclusively in a distinctive, apparently more nave state of pluripotency (the ground state) with inhibitors for mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i). Understanding the mechanism ensuring a nave state of pluripotency would be critical in realizing a full potential of ESCs. We show here that PRDM14, a PR domain-containing transcriptional regulator, ensures a nave 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.

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Yamaji M, Ueda J, Hayashi K, Ohta H, Yabuta Y, Kurimoto K, Nakato R, Yamada Y, Shirahige K, Saitou M