# Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation

## TL;DR

This paper shows how SOX2 protein levels control how cells respond to WNT signals during early development, influencing whether cells stay pluripotent or differentiate into mesoderm.

## Contribution

The study reveals that SOX2 expression levels dynamically regulate chromatin occupancy of WNT mediators, enabling distinct developmental outcomes in epiblast progenitors.

## Key findings

- High SOX2 levels maintain pluripotency by displacing nucleosomes and recruiting TCF/β-catenin to high-affinity sites.
- Reduced SOX2 levels shift TCF/β-catenin occupancy to caudal epiblast genes, co-occupied by T/Bra and CDX.
- Lower SOX2 allows WNT-induced mesodermal differentiation by reconfiguring chromatin interactions.

## Abstract

WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 displaces nucleosomes from regulatory elements with high-affinity SOX2 binding sites, recruiting the WNT effector TCF/β-catenin and maintaining pluripotent gene expression. Reducing SOX2 levels destabilizes pluripotency and reconfigures SOX2/TCF/β-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT-induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/β-catenin and reveal how context-specific responses to a signal are configured by the level of a transcription factor.

Blassberg et al. report that SOX2 levels determine the chromatin occupancy of TCF/β-catenin, thus orchestrating the WNT response and epiblast progenitor fate.