Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9.

Laurens M Van Tienen,Marc Fiedler,Mariann Bienz,Trevor J Rutherford,Juliusz Mieszczanek

doi:10.7554/elife.20882

Abstract

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.

Highlights

The Wnt/b-catenin signaling cascade is an ancient cell communication pathway that operates context-dependent transcriptional switches to control animal development and tissue homeostasis (Cadigan and Nusse, 1997)
Our study has uncovered genetic and physical interactions between two constitutive core components of the Wnt enhanceosome and the C-terminus of Legless/BCL9. The first of these is ChiLS, the core module of the Wnt enhanceosome (Fiedler et al, 2015) (Figure 7): we have shown that ChiLS is a direct and specific ligand of the a-helical homology domain 3 (HD3) element of B9L and, likely, of other Legless/BCL9 orthologs, given the strong sequence conservation of this a-helix (Figure 6)
Our evidence implicates HD3 as an evolutionary conserved contact point between Legless/BCL9 and ChiLS, the primary link between these two proteins appears to be provided by Pygo

Summary

Introduction

The Wnt/b-catenin signaling cascade is an ancient cell communication pathway that operates context-dependent transcriptional switches to control animal development and tissue homeostasis (Cadigan and Nusse, 1997). Absence of b-catenin defines the OFF state of these enhancers, which are silenced by Groucho/TLE co-repressors bound to TCF via their Q domain This domain tetramerizes to promote transcriptional repression (Chodaparambil et al, 2014), which leads to chromatin compaction (Sekiya and Zaret, 2007) apparently assisted by the interaction between Groucho/TLE and histone deacetylases (HDACs) (Jennings et al, 2008; Turki-Judeh and Courey, 2012). Wnt signaling relieves this repression by blocking the degradation of b-catenin, which accumulates and binds to TCF, converting the Wnt-responsive enhancers into the ON state.

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Results

Conclusion