# Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association

## TL;DR

Excessive mTORC1 activity blocks stem cell development by working with TFE3 and NuRD to silence key genes.

## Contribution

Identifies a shared mechanism involving TFE3 and NuRD in mTORC1-mediated repression of stem cell fate transitions.

## Key findings

- Hyperactivated mTORC1 causes TFE3 to move to the nucleus and recruit the NuRD complex.
- The TFE3-NuRD complex represses genes essential for stem cell fate transitions.
- This mechanism applies to both pluripotency exit and somatic cell reprogramming.

## Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.

The mTORC1-TFE3-NuRD axis mediates stem cell fate transitions by enabling TFE3 to recruit the NuRD complex and to repress genes essential for pluripotency exit and somatic cell reprogramming.

Hyperactivation of mTORC1 blocks pluripotency exit and somatic cell reprogramming by promoting nuclear translocation of TFE3.Nuclear TFE3 associates with the NuRD corepressor complex.The nuclear TFE3-NuRD complex directly binds to and represses genes critical for cell fate transitions.

Hyperactivation of mTORC1 blocks pluripotency exit and somatic cell reprogramming by promoting nuclear translocation of TFE3.

Nuclear TFE3 associates with the NuRD corepressor complex.

The nuclear TFE3-NuRD complex directly binds to and represses genes critical for cell fate transitions.

The mTORC1-TFE3-NuRD axis mediates stem cell fate transitions by enabling TFE3 to recruit the NuRD complex and to repress genes essential for pluripotency exit and somatic cell reprogramming.