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

Cell Reports, Vol. 36 (2021)

Keywords
Authors
  • Nikolaos Doumpas
  • Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
  • Simon Söderholm
  • Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
  • Smarth Narula
  • Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
  • Steven Moreira
  • Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
  • Bradley W. Doble
  • Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Departments of Biochemistry and Medical Genetics & Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3E 0W2, Canada
  • Claudio Cantù
  • Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Corresponding author
  • Konrad Basler
  • Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland; Corresponding author

Abstract

Summary: Mouse embryonic stem cells (mESCs) can be maintained in vitro in defined N2B27 medium supplemented with two chemical inhibitors for GSK3 and MEK (2i) and the cytokine leukemia inhibitory factor (LIF), which act synergistically to promote self-renewal and pluripotency. Here, we find that genetic deletion of the four genes encoding the TCF/LEF transcription factors confers mESCs with the ability to self-renew in N2B27 medium alone. TCF/LEF quadruple knockout (qKO) mESCs display dysregulation of several genes, including Aire, Dnmt3l, and IcosL, located adjacent to each other within a topologically associated domain (TAD). Aire, Dnmt3l, and IcosL appear to be regulated by TCF/LEF in a β-catenin independent manner. Moreover, downregulation of Aire and Dnmt3l in wild-type mESCs mimics the loss of TCF/LEF and increases mESC survival in the absence of 2iL. Hence, this study identifies TCF/LEF effectors that mediate exit from the pluripotent state.

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