# OTX2 controls chromatin accessibility to direct somatic versus germline differentiation

## TL;DR

OTX2 influences whether cells become somatic or germline by controlling chromatin accessibility in early embryonic cells.

## Contribution

OTX2 is shown to act as a pioneer factor that opens chromatin at somatic-associated regions, promoting somatic differentiation.

## Key findings

- OTX2 binds and opens chromatin at specific loci to enable somatic differentiation.
- Enforced OTX2 expression induces opening of ~4000 somatic-associated regions even in the presence of germline-inducing cytokines.
- Once cells adopt germline identity, these somatic regions become unresponsive to OTX2.

## Abstract

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 this process, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. Yet, how OTX2 achieves this function is not fully characterised. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to enable somatic differentiation. CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs identifies regions where OTX2 binds and opens chromatin. Enforced OTX2 expression maintains accessibility at these regions and also induces opening of ~4000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional regions no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline.

The transcription factor OTX2 regulates the choice between somatic and germline differentiation by opening chromatin at somatic-associated regulatory regions.

The transcription factor OTX2 acts as a pioneer factor to induce somatic differentiation in formative stem cells.Enforced expression of OTX2 induces opening of additional somatic-associated regions in presence of germline-inducing cytokines.These additional regions become refractory to OTX2 presence when cells have acquired germline identity.

The transcription factor OTX2 acts as a pioneer factor to induce somatic differentiation in formative stem cells.

Enforced expression of OTX2 induces opening of additional somatic-associated regions in presence of germline-inducing cytokines.

These additional regions become refractory to OTX2 presence when cells have acquired germline identity.

The transcription factor OTX2 regulates the choice between somatic and germline differentiation by opening chromatin at somatic-associated regulatory regions.