Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9

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.DOI: http://dx.doi.org/10.7554/eLife.20882.001

Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

“…Other studies have identified additional regulatory complexes, such as the DOTCOM complex, that contribute to β‐catenin regulation of transcription (Mohan et al, ), but complexes such as these are more broadly acting and are not necessarily dedicated to β‐catenin‐TCF/LEF complexes (Cadigan and Waterman, ). More recently, there have been exciting advances in identifying the specific complex of proteins established by TCF/LEFs on chromatin and understanding how that complex is modified by Wnt signalling and β‐catenin (Chodaparambil et al, ; Fiedler et al, ; van Tienen et al, ) (Figure ). The old model of β‐catenin displacing Groucho/TLE repressors from TCF/LEFs to activate gene expression clearly needs refinement as current studies suggest that co‐repressors and co‐activators might exist simultaneously.…”

“…As discussed at the beginning of this section, the TCF/LEF–β‐catenin transcriptional complex has been found to be tightly regulated in a context‐dependent manner by different co‐regulatory factors that assemble at WREs in promoters and enhancers of target genes (Figure ) (Levanon et al, ; Waltzer and Bienz, ; Hecht et al, ; Sun et al, ; Takemaru and Moon, ; Brantjes et al, ; Chodaparambil et al, ; Fiedler et al, ; van Tienen et al, ). These findings have led to a ‘Wnt enhanceosome model’ (Fiedler et al, ).…”

“…It is this enhanceosome complex that captures newly stabilized, nuclear‐localized β‐catenin. The binding of β‐catenin then triggers structural rearrangements to BCL9, negates TLE repressive functions and activates the TCF/LEF–β‐catenin transcriptional complex and transcription of Wnt target genes (Chodaparambil et al, ; Fiedler et al, ; van Tienen et al, ). Based on this model, one potential strategy for future drug development would be to design small molecule inhibitors that disrupt key protein‐protein interactions that drive the activity of the Wnt enhanceosome complex.…”

The Wnt Transcriptional Switch: TLE Removal or Inactivation?

“…A) As described by Franz et al, many Wnt target genes show no evidence of TCF/Pan dependent repression in the absence of Wnt signaling. B) Model proposed in van Tienen et al, where in the absence of Wnt signaling, TLE, BCL9/B9L, and Pygo proteins co‐occupy W‐CRMs. C) This model postulated that these factors are also associated with TCF in Wnt‐stimulated cells, along with β‐catenin and other co‐activators.…”

“…Interestingly, Pygo also associates with Gro in flies, and analysis of gro , pygo double mutants suggests that a major function of Pygo is to inactivate Gro . A recent study examined proteins associated with biotin ligase‐tagged BCL9 and B9L, in the presence and absence of Wnt signaling using a technique called BioID. Surprisingly, the authors found both BCL9 and B9L associated with TLEs irrespective of the state of Wnt signaling in HEK293 cells.…”