PRDM14 Controls Sensitivity to Extrinsic Signals and Ensures a Naïve Epigenome in Mouse Embryonic Stem Cells
Understanding the mechanism controlling the embryonic stem cell (ESC) state is critical in stem cell biology. We show here that PRDM14, a PR domain-containing transcriptional regulator, is essential for mouse ESC (mESC) derivation in serum.  However, with inhibitors for MAPKK and GSK3 (2i), Prdm14-deficient ESC-like cells are established. These cells exhibit pluripotency, but are vulnerable to differentiation due to hyperactive FGFR signalling, many components of which are targets for repression by PRDM14. These cells also de-repress de novo DNA methyltransferases DNMT3A, DNMT3B and DNMT3L, and show enhanced DNA methylation and repression of Tcl1, resulting in reduced AKT-mTORC1 activity and retarded proliferation. The hyper-methylation in Prdm14-deficient cells is global and similar to the methylation in pre-gastrulating epiblasts or the epiblast-like cells (EpiLCs). Importantly, regulation of DNA methylation involving PRDM14 shows metastability. PRDM14 associates with PRC2. These findings reveal a mechanism that controls sensitivity to extrinsic signals and ensures a naïve epigenome of mESCs.