title: An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP.
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.
authors: MRC Laboratory of Molecular Biology, , Cambridge, United Kingdom.
authors: Marc
authors: M
authors: Fiedler
authors: MRC Laboratory of Molecular Biology, , Cambridge, United Kingdom.
authors: Michael
authors: M
authors: Graeb
authors: MRC Laboratory of Molecular Biology, , Cambridge, United Kingdom.
authors: Juliusz
authors: J
authors: Mieszczanek
authors: MRC Laboratory of Molecular Biology, , Cambridge, United Kingdom.
authors: Trevor J
authors: TJ
authors: Rutherford
authors: MRC Laboratory of Molecular Biology, , Cambridge, United Kingdom.
authors: Christopher M
authors: CM
authors: Johnson
authors: MRC Laboratory of Molecular Biology, , Cambridge, United Kingdom.
authors: Mariann
authors: M
authors: Bienz
mesh_terms: D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C108740:Chi protein, Drosophila; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C520429:Ssdp protein, Drosophila; D014157:Transcription Factors; C453400:pygo protein, Drosophila
keywords: D. melanogaster; LIM domain-binding protein; Osa/ARID1; RUNX; Wnt-responsive transcription; beta-catenin; biophysics; developmental biology; groucho/TLE; human; stem cells; structural biology