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Updated: May 12, 2026

A Two-Step Strategy that Combines Epigenetic Modification and Biomechanical Cues to Generate Mammalian Pluripotent Cells
08:01

A Two-Step Strategy that Combines Epigenetic Modification and Biomechanical Cues to Generate Mammalian Pluripotent Cells

Published on: August 29, 2020

Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3

Joerg Betschinger1, Jennifer Nichols, Sabine Dietmann

  • 1Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. jb579@cam.ac.uk

Cell
|April 16, 2013
PubMed

Insights

Tumor suppressors Folliculin (Flcn) and Tsc2 prevent embryonic stem cell (ESC) commitment by regulating Tfe3. Enforced nuclear Tfe3 maintains pluripotency, revealing a rheostat for lineage commitment.

Area of Science:

  • Stem cell biology
  • Molecular mechanisms of pluripotency
  • Cell fate determination

Background:

  • Self-renewal of mouse embryonic stem cells (ESCs) is well-understood.
  • The molecular machinery controlling exit from pluripotency remains poorly defined.

Purpose of the Study:

  • To identify factors regulating exit from pluripotency in ESCs.
  • To elucidate the role of Folliculin (Flcn) and Tsc2 in ESC commitment.

Main Methods:

  • Large-scale small interfering RNA (siRNA) screen.
  • Analysis of mammalian target of rapamycin (mTOR) pathway.
  • Investigation of transcription factor Tfe3 localization and activity.
  • Genome-wide location and functional analyses.
  • In vivo studies of epiblast development.

Main Results:

  • Knockdown of Flcn and Tsc2 prevents ESC commitment.
  • Flcn, with Fnip1/2, restricts nuclear Tfe3, promoting differentiation.
  • Enforced nuclear Tfe3 allows ESCs to resist differentiation.
  • Tfe3 directly regulates Esrrb, integrating into the pluripotency circuitry.
  • Flcn-Fnip1/2 influences Tfe3 localization during in vivo development.

Conclusions:

  • Flcn-Tsc2-mTOR pathway and Flcn-Fnip1/2-Tfe3 axis act as a cell-intrinsic rheostat for pluripotency destabilization.
  • Tfe3 is a key regulator integrating pluripotency and differentiation.
  • Flcn-mediated regulation of Tfe3 is crucial for developmental progression of the epiblast.

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