# Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation

## TL;DR

The study shows how the pioneer transcription factor GATA6 interacts with other factors to reprogram cell identity and promote differentiation by altering chromatin structure and gene regulation.

## Contribution

The paper reveals how GATA6 dynamically interacts with other transcription factors to orchestrate nucleosome remodeling and cell differentiation.

## Key findings

- GATA6 transiently binds accessible regions to silence pluripotency genes and decommission enhancers.
- GATA6 initiates chromatin remodeling by creating fragile nucleosomes and increasing accessibility.
- OCT4 depletion during GATA6 induction impairs differentiation and alters GATA6 and SOX17 binding.

## Abstract

Pioneer transcription factors (TF) bind nucleosome-embedded DNA motifs to activate new regulatory elements and promote differentiation. However, the complexity, binding dependencies and temporal effects of their action remain unclear. Here, we dissect how ectopic induction of the pioneer TF GATA6 triggers Primitive Endoderm (PrE) differentiation from pluripotent cells. We show that transient GATA6 binding exploits accessible regions to decommission enhancers and promote pluripotency gene silencing. Simultaneously, GATA6 targets closed chromatin and initiates extensive remodeling culminating in the establishment of fragile nucleosomes flanked by ordered nucleosome arrays and increased accessibility. This is enhanced by rapidly expressed PrE TFs (SOX17) and by pluripotency TFs repurposed for differentiation (OCT4/SOX2). Accordingly, depletion of OCT4 during GATA6 induction decreases Gata6 expression, alters GATA6 and SOX17 binding and impairs differentiation. Therefore, pioneer TFs orchestrate complex regulatory networks involving many if not all available pioneer TFs, including those required to support the original identity of differentiating cells.

Here the authors describe how a pioneer TF reprograms cell identity, highlighting how it establishes new networks building on the set of key TFs present in the cell, pre-existing nucleosome fragility and sculpting chromatin-TF interactions over time.