PRDM14 drives OCT3/4 recruitment via active demethylation in the transition from primed to naïve pluripotency

Primordial germ cells (PGCs) are specified from epiblast cells in mice. Genes associated with naïve pluripotency are transiently repressed in the transition from inner cell mass (ICM) to epiblast cells, followed by their upregulation soon after PGC specification. However, the molecular mechanisms underlying the reactivation of pluripotency genes are poorly characterized. Here, we exploited in vitro differentiation of epiblast-like cells (EpiLCs) from embryonic stem cells (ESCs) to elucidate the molecular and epigenetic functions of PR domain-containing 14 (PRDM14). We found that Prdm14 overexpression in EpiLCs induced their conversion to ESC-like cells even in the absence of leukemia inhibitory factor (LIF). This was impaired by the loss of Kruppel-like factor 2 (Klf2) and ten-eleven translocation (TET) proteins. Furthermore, PRDM14 recruited OCT3/4 to the enhancer regions of naïve pluripotency genes via TET-base excision-repair-mediated demethylation. Our results provide evidence that PRDM14 establishes a transcriptional network for naïve pluripotency via active DNA demethylation. To investigate the function of TET1/TET2 in the transition form primed to naïve pluripotency, we exploited microarray analysis using total mRNA derived from Scramble, Scramble + PRDM14, Tet1/Tet2 KD, Tet1/Tet2 KD + PRDM14 mouse ESCs and EpiLCs.