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

Nature Cell Biology volume 13, pages 762770 (2011) | Download Citation

Abstract

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.

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Acknowledgements

We thank K. Plath for helpful discussions and thoughtful comments on the manuscript, and M. Ko and A. Nishiyama for the inducible Tcf3 overexpression cell line. The work was financially supported by grants from the American Cancer Society (RSG GGC 112994, B.J.M.), the National Institutes of Health (R01-CA128571, B.J.M. and R01-GM065400, D.R.L.) and the Howard Hughes Medical Institute (D.R.L.).

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Author notes

    • Fei Yi
    •  & Laura Pereira

    These authors contributed equally to this manuscript

Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland Avenue, MBRB 2270, M/C 669, Chicago, Illinois 60607, USA

    • Fei Yi
    • , Laura Pereira
    • , Jackson A. Hoffman
    • , Brian R. Shy
    •  & Bradley J. Merrill
  2. Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA

    • Courtney M. Yuen
    •  & David R. Liu

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Contributions

All authors designed and analysed experiments. F.Y., L.P., J.A.H., B.R.S. and C.M.Y. carried out experiments. F.Y., L.P. and B.J.M. wrote the manuscript. B.J.M. and D.R.L. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bradley J. Merrill.

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https://doi.org/10.1038/ncb2283

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