The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling

Sara Kassel, Kai Yuan, Nawat Bunnag, Leif R. Neitzel, Wenhui Lu, Anna Schwarzkopf, Benjamin Maines, Matthew A. Loberg, George Xu, Amber Adams, Andrew D. McCray, Alex Cho, Mary Rockouski, Gemma Orton, Lily Goldsmith, Md Mubtaseem Ahnaf Aronno, Zachary T. Spencer, Omar M. Khan, Fei Ye, Charles Williams, Andres M. Lebensohn, Rajat Rohatgi, Xiaofeng Wang, Vivian L. Weiss, Charles C. Hong, Arminja N. Kettenbach, David J. Robbins, Yashi Ahmed () and Ethan Lee ()
Additional contact information
Sara Kassel: Vanderbilt University
Kai Yuan: Dartmouth College
Nawat Bunnag: Dartmouth College
Leif R. Neitzel: Michigan State University College of Human Medicine
Wenhui Lu: Georgetown University
Anna Schwarzkopf: Vanderbilt University
Benjamin Maines: Dartmouth College
Matthew A. Loberg: Vanderbilt University Medical Center
George Xu: Vanderbilt University Medical Center
Amber Adams: Dartmouth College
Andrew D. McCray: Dartmouth College
Alex Cho: Vanderbilt University
Mary Rockouski: Vanderbilt University
Gemma Orton: Vanderbilt University
Lily Goldsmith: Vanderbilt University
Md Mubtaseem Ahnaf Aronno: Dartmouth College
Zachary T. Spencer: Dartmouth College
Omar M. Khan: Hamad Bin Khalifa University
Fei Ye: Vanderbilt University Medical Center
Charles Williams: Michigan State University College of Human Medicine
Andres M. Lebensohn: National Institutes of Health
Rajat Rohatgi: Stanford University School of Medicine
Xiaofeng Wang: Dartmouth College
Vivian L. Weiss: Vanderbilt University Medical Center
Charles C. Hong: Michigan State University College of Human Medicine
Arminja N. Kettenbach: Dartmouth College
David J. Robbins: Georgetown University
Yashi Ahmed: Dartmouth College
Ethan Lee: Vanderbilt University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes displace nucleosomes to promote the access of transcription factors to enhancers and promoters. Despite the critical roles of SWI/SNF in animal development and tumorigenesis, how signaling pathways recruit SWI/SNF complexes to their target genes is unclear. Here, we demonstrate that target gene activation mediated by β-catenin, the essential transcriptional coactivator in the Wnt signal transduction pathway, requires ubiquitylation of the SWI/SNF component Brahma-related gene-1 (BRG1) by the E3 ubiquitin ligase Thyroid Hormone Receptor Interactor 12 (TRIP12). TRIP12 depletion in Drosophila, zebrafish, mouse organoids, and human cells attenuates Wnt signaling. Genetic epistasis experiments place TRIP12 activity downstream of the β-catenin destruction complex. TRIP12 interacts with and ubiquitylates BRG1, and BRG1 depletion blocks TRIP12-mediated Wnt pathway activation. TRIP12 promotes BRG1 binding to β-catenin in the presence of Wnt. Our findings support a model in which TRIP12 ubiquitylates BRG1 in the presence of Wnt and promotes its interaction with β-catenin in the nucleus, in order to recruit SWI/SNF to Wnt target genes. Our studies suggest a general mechanism by which cell signaling induces the interaction between BRG1 and pathway-specific transcription factors to recruit SWI/SNF complexes to their appropriate target genes.

Date: 2025
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DOI: 10.1038/s41467-025-60535-5

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