# TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1

## TL;DR

This study shows how a TGFβ-driven metabolic switch helps human stem cells become endoderm by boosting TCA cycle activity and ATP-dependent chromatin changes.

## Contribution

The study identifies PDHB-mediated metabolic reprogramming as a novel mechanism for ATP-dependent endoderm differentiation via BRG1.

## Key findings

- TGFβ-driven metabolic changes enhance TCA cycle activity and oxidative phosphorylation during endoderm differentiation.
- Reduced lactate production and increased ATP levels are essential for BAF complex activity and endoderm gene activation.
- Disrupting glucose or pyruvate metabolism impairs endoderm differentiation efficiency.

## Abstract

Cell fate determination is closely linked to metabolic state, yet how metabolic remodeling influences human pluripotent stem cells differentiation into three germ layers remains incompletely understood. Here, we reveal that definitive endoderm differentiation from human pluripotent stem cells requires a TGFβ-driven metabolic switch characterized by reduced lactate production and enhanced TCA cycle activity and oxidative phosphorylation, mediated by PDHB. Disruption of glucose utilization or pyruvate entry into the TCA cycle markedly impairs endoderm differentiation, whereas inhibition of lactate production enhances differentiation efficiency. Mechanistically, blockade of glucose metabolism or the TCA cycle reduces intracellular ATP levels, compromising the activity of BAF complex, an ATP-dependent chromatin remodeling complex centered on BRG1. This complex promotes chromatin accessibility and activates endodermal gene programs during differentiation. Together, these findings highlight metabolic reprogramming as a key regulator of human endoderm fate through ATP-dependent control of chromatin remodeling.

How metabolic changes regulate human endoderm differentiation remains unclear. Here, the authors show that a TGFβ-driven metabolic switch reduces lactate production and enhances the TCA cycle, which controls ATP-dependent BAF complex activity to promote definitive endoderm differentiation.