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TCF/LEF regulation of the topologically associated domain ADI promotes mESCs to exit the pluripotent ground state

Nikolaos Doumpas1, Simon Söderholm2, Smarth Narula3

  • 1Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.

Cell Reports
|September 15, 2021
PubMed

Insights

Deleting TCF/LEF transcription factors allows mouse embryonic stem cells (mESCs) to self-renew without specific inhibitors. This finding reveals key regulators controlling pluripotency exit.

Area of Science:

  • Stem cell biology
  • Molecular genetics
  • Epigenetics

Background:

  • Mouse embryonic stem cells (mESCs) require specific conditions (N2B27 medium with 2i inhibitors and LIF) for self-renewal and pluripotency.
  • Transcription factors play crucial roles in regulating stem cell fate.

Purpose of the Study:

  • To investigate the role of TCF/LEF transcription factors in mESC self-renewal.
  • To identify downstream targets of TCF/LEF that regulate pluripotency.

Main Methods:

  • Genetic deletion of TCF/LEF genes in mESCs (quadruple knockout, qKO).
  • Culture of mESCs in defined N2B27 medium without 2i/LIF.
  • Analysis of gene expression and regulation within topologically associated domains (TADs).

Main Results:

  • TCF/LEF quadruple knockout mESCs self-renew in N2B27 medium alone.
  • Dysregulation of Aire, Dnmt3l, and IcosL genes in qKO mESCs, located within the same TAD.
  • TCF/LEF regulation of these genes occurs independently of β-catenin.
  • Downregulation of Aire and Dnmt3l in wild-type mESCs enhances survival without 2i/LIF, mimicking TCF/LEF loss.

Conclusions:

  • TCF/LEF transcription factors are essential for mediating the exit from the pluripotent state in mESCs.
  • Aire, Dnmt3l, and IcosL are identified as key TCF/LEF effectors involved in pluripotency regulation.
  • Understanding TCF/LEF function provides insights into maintaining stem cell identity and differentiation pathways.
Keywords:
TCF/LEFWnt signalingmESCpluripotencyβ-catenin

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