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

Wnt/b-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 read and acting through TCF/LEF responsive enhancers. Pygo renders this complex Wnt-responsive, by capturing beta-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 beta-catenin to the enhanceosome apparently causes 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 beta-catenin co-factors may coordinate Wnt and nuclear hormone responses.