1. Structural Biology and Molecular Biophysics
  2. Developmental Biology

An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP

  1. Marc Fiedler
  2. Michael Graeb
  3. Juliusz Mieszczanek
  4. Trevor J Rutherford
  5. Christopher M Johnson
  6. Mariann Bienz  Is a corresponding author
  1. Medical Research Council, United Kingdom
https://doi.org/10.7554/eLife.09073
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  1. Marc Fiedler
  2. Michael Graeb
  3. Juliusz Mieszczanek
  4. Trevor J Rutherford
  5. Christopher M Johnson
  6. Mariann Bienz
(2015)
An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP
eLife 4:e09073.
https://doi.org/10.7554/eLife.09073
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Abstract

TCF/LEF factors are ancient context-dependent enhancer-binding proteins that are activated by β-catenin following Wnt signaling. They control embryonic development and adult stem cell compartments, and their dysregulation often causes cancer. β-catenin-dependent transcription relies on the NPF motif of Pygo proteins. Here, we use a proteomics approach to discover the Chip/LDB-SSDP (ChiLS) complex as the ligand specifically binding to NPF. ChiLS also recognizes NPF motifs in other nuclear factors including Runt/RUNX2 and Drosophila ARID1, and binds to Groucho/TLE. Studies of Wnt-responsive dTCF enhancers in the Drosophila embryonic midgut indicate how these factors interact to form the Wnt enhanceosome, primed for Wnt responses by Pygo. Together with previous evidence, our study indicates that ChiLS confers context-dependence on TCF/LEF by integrating multiple inputs from lineage and signal-responsive factors, including enhanceosome switch-off by Notch. Its pivotal function in embryos and stem cells explain why its integrity is crucial in the avoidance of cancer.

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  1. Marc Fiedler

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Michael Graeb

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Juliusz Mieszczanek

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Trevor J Rutherford

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Christopher M Johnson

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Mariann Bienz

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    For correspondence
    mb2@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Fiedler et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Marc Fiedler
  2. Michael Graeb
  3. Juliusz Mieszczanek
  4. Trevor J Rutherford
  5. Christopher M Johnson
  6. Mariann Bienz
(2015)
An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP
eLife 4:e09073.
https://doi.org/10.7554/eLife.09073

Share this article

https://doi.org/10.7554/eLife.09073

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Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology

    Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9

    Laurens M van Tienen, Juliusz Mieszczanek ... Mariann Bienz
    Research Article

    Wnt/β-catenin signaling elicits context-dependent transcription switches that determine normal development and oncogenesis. These are mediated by the Wnt enhanceosome, a multiprotein complex binding to the Pygo chromatin reader and acting through TCF/LEF-responsive enhancers. Pygo renders this complex Wnt-responsive, by capturing β-catenin via the Legless/BCL9 adaptor. We used CRISPR/Cas9 genome engineering of Drosophila legless (lgs) and human BCL9 and B9L to show that the C-terminus downstream of their adaptor elements is crucial for Wnt responses. BioID proximity labeling revealed that BCL9 and B9L, like PYGO2, are constitutive components of the Wnt enhanceosome. Wnt-dependent docking of β-catenin to the enhanceosome apparently causes a rearrangement that apposes the BCL9/B9L C-terminus to TCF. This C-terminus binds to the Groucho/TLE co-repressor, and also to the Chip/LDB1-SSDP enhanceosome core complex via an evolutionary conserved element. An unexpected link between BCL9/B9L, PYGO2 and nuclear co-receptor complexes suggests that these β-catenin co-factors may coordinate Wnt and nuclear hormone responses.