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由无腿蛋白/BCL9对多个Wnt增强体组件进行组成型支架构建。

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

作者信息

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

机构信息

MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.

出版信息

Elife. 2017 Mar 15;6:e20882. doi: 10.7554/eLife.20882.

DOI:10.7554/eLife.20882
PMID:28296634
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5352222/
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 and human and 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.

摘要

Wnt/β-连环蛋白信号传导引发依赖于背景的转录开关，这些开关决定正常发育和肿瘤发生。这些是由Wnt增强体介导的，Wnt增强体是一种多蛋白复合物，与Pygo染色质阅读器结合并通过TCF/LEF反应性增强子起作用。Pygo通过无腿蛋白/BCL9衔接子捕获β-连环蛋白，使该复合物对Wnt产生反应。我们使用CRISPR/Cas9基因组工程对小鼠和人类的Pygo2及Pygo1进行研究，结果表明其衔接子元件下游的C末端对Wnt反应至关重要。生物ID邻近标记显示，与PYGO2一样，BCL9和B9L是Wnt增强体的组成成分。β-连环蛋白与增强体的Wnt依赖性对接显然会导致一种重排，使BCL9/B9L的C末端与TCF并列。该C末端与Groucho/TLE共抑制因子结合，还通过一个进化保守元件与Chip/LDB1-SSDP增强体核心复合物结合。BCL9/B9L、PYGO2与核共受体复合物之间存在意外联系，这表明这些β-连环蛋白辅助因子可能协调Wnt和核激素反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/6446cd4e6b68/elife-20882-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/440c490d7fc4/elife-20882-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/6eee2381122a/elife-20882-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/7a98fbb00093/elife-20882-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/9a6054248073/elife-20882-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/0b29bc70973d/elife-20882-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/944f9b6335c3/elife-20882-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/91044eff7633/elife-20882-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/c6e8fbb2a7b5/elife-20882-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/6446cd4e6b68/elife-20882-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/440c490d7fc4/elife-20882-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/6eee2381122a/elife-20882-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/7a98fbb00093/elife-20882-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/9a6054248073/elife-20882-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/0b29bc70973d/elife-20882-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/944f9b6335c3/elife-20882-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/91044eff7633/elife-20882-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/c6e8fbb2a7b5/elife-20882-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53a4/5352222/6446cd4e6b68/elife-20882-fig4-figsupp2.jpg

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