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Updated: Jan 22, 2026

Fate Mapping of Human Embryonic Stem Cells by Teratoma Formation
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Fate Mapping of Human Embryonic Stem Cells by Teratoma Formation

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

Peizhi Li1,2, Shuhui Xu1,3, Xinyu Wu1

  • 1Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, 510530, China.

EMBO Reports
|January 20, 2026
PubMed

Insights

Mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation blocks stem cell reprogramming by promoting TFE3 nuclear translocation. TFE3 then recruits NuRD to repress key genes, revealing a shared mechanism controlling cell fate.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Stem Cell Biology

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth and metabolism, integrating nutrient and growth factor signals.
  • Dysregulated mTORC1 signaling disrupts stem cell homeostasis and impairs cell fate transitions, impacting development, aging, and diseases like cancer.
  • Previous research indicated mTORC1 hyperactivation blocks pluripotency exit and somatic cell reprogramming, but the underlying transcriptional mechanisms were unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which mTORC1 hyperactivation controls gene transcription during stem cell transitions.
  • To investigate the role of TFE3 in mediating the transcriptional blockade induced by mTORC1 during pluripotency exit and somatic cell reprogramming.

Main Methods:

  • Utilized mouse and human naïve embryonic stem cells.
  • Investigated the nuclear translocation of TFE3.
  • Analyzed the recruitment of the NuRD corepressor complex.
  • Examined the repression of genes critical for cell fate transitions.

Main Results:

  • Demonstrated that TFE3 mediates the transcriptional blockade caused by mTORC1 hyperactivation during reprogramming.
  • Showed that TFE3 translocates to the nucleus upon mTORC1 hyperactivation, blocking pluripotency exit.
  • Confirmed that TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions during both pluripotency exit and reprogramming.

Conclusions:

  • Uncovered a shared mechanism involving mTORC1 and TFE3 in regulating stem cell identity and fate.
  • Highlighted the dual role of TFE3 as a transcriptional regulator in controlling cell fate transitions.
  • Suggests potential implications of this regulatory pathway in development, aging, and tumorigenesis.
Keywords:
NuRD ComplexPluripotency ExitSomatic Cell ReprogrammingTFE3mTORC1

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