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Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal.

The co-occupancy of Tcf3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that Tcf3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signalling suggested Tcf3-β-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression regulates ESC self-renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of Tcf3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both Tcf3-β-catenin and Tcf1-β-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized β-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network.

Pubmed ID: 21685894

Authors

  • Yi F
  • Pereira L
  • Hoffman JA
  • Shy BR
  • Yuen CM
  • Liu DR
  • Merrill BJ

Journal

Nature cell biology

Publication Data

July 4, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA128571
  • Agency: NIGMS NIH HHS, Id: R01 GM065400
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-01
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-02
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-03
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-04
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-05
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-06
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-07
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-08
  • Agency: NIGMS NIH HHS, Id: R01 GM065400-09
  • Agency: NCI NIH HHS, Id: R01-CA128571
  • Agency: NIGMS NIH HHS, Id: R01-GM065400
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Line
  • Cell Proliferation
  • Embryonic Stem Cells
  • Gene Expression Regulation, Developmental
  • Glycogen Synthase Kinase 3
  • Hepatocyte Nuclear Factor 1-alpha
  • Homeodomain Proteins
  • Mice
  • Octamer Transcription Factor-3
  • Protein Kinase Inhibitors
  • RNA Interference
  • SOXB1 Transcription Factors
  • Signal Transduction
  • Transcription, Genetic
  • Transfection
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin