OTX2 controls chromatin accessibility to direct somatic versus germline differentiation

The choice between somatic and germline fates is essential for species survival. This choice occurs in embryonic epiblast cells, as these cells are competent for both somatic and germline differentiation. The transcription factor OTX2 regulates the choice between somatic and germline fates, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. However, the mechanisms by which OTX2 achieves this function are not fully characterized. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to modulate gene transcription and enable somatic differentiation. By performing CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs, we identified regions where OTX2 binding opens chromatin, either alone or in cooperation with a ZIC family protein. Enforced OTX2 expression maintains accessibility at these regions and, in addition, induces opening of [~]4,000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional somatic-associated regions can no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for both somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline.