# Nanog mediated control of TBX3-GATA6 circuitry in primitive endoderm differentiation of mESCs

## TL;DR

The study reveals how NANOG, TBX3, and GATA6 work together to control cell fate decisions in mouse embryonic stem cells.

## Contribution

It identifies a regulatory axis involving NANOG, TBX3, and GATA6 that integrates enhancer control and chromatin regulation during lineage commitment.

## Key findings

- NANOG partners with TBX3 and PRC2 to silence PrE genes via distal enhancers.
- Loss of Nanog allows TBX3 to switch to GATA6, driving PrE differentiation.
- Combined deletion of Nanog and Tbx3 reduces PrE gene expression but GATA6 sustains residual activity.

## Abstract

Cell fate decisions in the early embryo rely on reciprocal transcriptional networks that balance pluripotency with lineage commitment. NANOG is essential for directing the epiblast–primitive endoderm (PrE) fate choice, but the molecular mechanisms underlying its repressive activity remain incompletely understood. Here we show that NANOG partners with TBX3 and the PRC2 complex to maintain embryonic stem cell (ESC) identity by silencing PrE genes through newly identified distal enhancers. Loss of Nanog reduces PRC2-mediated repression of Gata6, initiating its expression independently of TBX3. Subsequent TBX3 upregulation enables its association with GATA6, driving a feed-forward programme that activates Gata6, Gata4 and Sox17 and promotes PrE differentiation. Thus, NANOG suppresses PrE fate not only by direct repression but also by preventing TBX3 from switching partners. These findings define a Nanog–Tbx3–Gata6 regulatory axis that integrates enhancer control, chromatin regulation and transcription factor redeployment to couple ESC maintenance with lineage commitment.

A NANOG–TBX3–GATA6 regulatory network controls primitive endoderm fate of mouse ESCs by coupling enhancer repression, chromatin regulation, and transcription factor redeployment. Loss of Nanog disrupts this network, enabling TBX3–GATA6 cooperation to drive PrE gene activation.

NANOG partners with TBX3 and the PRC2 complex to maintain ESC identity by silencing PrE genes through newly identified distal enhancers.TBX3 functions as a context-dependent cofactor whose partner switching—from NANOG to GATA6—redirects enhancer activity and couples ESC maintenance to lineage commitment.Combined deletion of Nanog and Tbx3 diminishes PrE transcriptional output, yet persistent GATA6 occupancy sustains residual gene expression, revealing a hierarchical Nanog–Tbx3–Gata6 regulatory axis in ESC fate control.

NANOG partners with TBX3 and the PRC2 complex to maintain ESC identity by silencing PrE genes through newly identified distal enhancers.

TBX3 functions as a context-dependent cofactor whose partner switching—from NANOG to GATA6—redirects enhancer activity and couples ESC maintenance to lineage commitment.

Combined deletion of Nanog and Tbx3 diminishes PrE transcriptional output, yet persistent GATA6 occupancy sustains residual gene expression, revealing a hierarchical Nanog–Tbx3–Gata6 regulatory axis in ESC fate control.

A NANOG–TBX3–GATA6 regulatory network controls primitive endoderm fate of mouse ESCs by coupling enhancer repression, chromatin regulation, and transcription factor redeployment. Loss of Nanog disrupts this network, enabling TBX3–GATA6 cooperation to drive PrE gene activation.