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; Ethan Lee

doi:10.1038/s41467-025-60535-5

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 WilliamsAndres M. Lebensohn, Rajat Rohatgi, Xiaofeng Wang, Vivian L. Weiss, Charles C. Hong, Arminja N. Kettenbach, David J. Robbins, Yashi Ahmed^*, Ethan Lee^*

^*Corresponding author for this work

Biological and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	5248
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-60535-5
Publication status	Published - 5 Jun 2025

Keywords

Beta-catenin
Cancer
Chromatin remodeling complexes
Drosophila
Genes
Long-range action
Receptor
Transcription factor
Ubiquitin ligase
Zebrafish

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10.1038/s41467-025-60535-5

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Kassel, S., Yuan, K., Bunnag, N., Neitzel, L. R., Lu, W., Schwarzkopf, A., Maines, B., Loberg, M. A., Xu, G., Adams, A., McCray, A. D., Cho, A., Rockouski, M., Orton, G., Goldsmith, L., Aronno, M. M. A., Spencer, Z. T., Khan, O. M., Ye, F., ... Lee, E. (2025). The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling. Nature Communications, 16(1), Article 5248. https://doi.org/10.1038/s41467-025-60535-5

@article{cf5934cc6c324d31967366dfd08a86e1,

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

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.",

keywords = "Beta-catenin, Cancer, Chromatin remodeling complexes, Drosophila, Genes, Long-range action, Receptor, Transcription factor, Ubiquitin ligase, Zebrafish",

author = "Sara Kassel and Kai Yuan and Nawat Bunnag and Neitzel, \{Leif R.\} and Wenhui Lu and Anna Schwarzkopf and Benjamin Maines and Loberg, \{Matthew A.\} and George Xu and Amber Adams and McCray, \{Andrew D.\} and Alex Cho and Mary Rockouski and Gemma Orton and Lily Goldsmith and Aronno, \{Md Mubtaseem Ahnaf\} and Spencer, \{Zachary T.\} and Khan, \{Omar M.\} and Fei Ye and Charles Williams and Lebensohn, \{Andres M.\} and Rajat Rohatgi and Xiaofeng Wang and Weiss, \{Vivian L.\} and Hong, \{Charles C.\} and Kettenbach, \{Arminja N.\} and Robbins, \{David J.\} and Yashi Ahmed and Ethan Lee",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jun,

day = "5",

doi = "10.1038/s41467-025-60535-5",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Kassel, S, Yuan, K, Bunnag, N, Neitzel, LR, Lu, W, Schwarzkopf, A, Maines, B, Loberg, MA, Xu, G, Adams, A, McCray, AD, Cho, A, Rockouski, M, Orton, G, Goldsmith, L, Aronno, MMA, Spencer, ZT, Khan, OM, Ye, F, Williams, C, Lebensohn, AM, Rohatgi, R, Wang, X, Weiss, VL, Hong, CC, Kettenbach, AN, Robbins, DJ, Ahmed, Y & Lee, E 2025, 'The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling', Nature Communications, vol. 16, no. 1, 5248. https://doi.org/10.1038/s41467-025-60535-5

TY - JOUR

T1 - The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling

AU - Kassel, Sara

AU - Yuan, Kai

AU - Bunnag, Nawat

AU - Neitzel, Leif R.

AU - Lu, Wenhui

AU - Schwarzkopf, Anna

AU - Maines, Benjamin

AU - Loberg, Matthew A.

AU - Xu, George

AU - Adams, Amber

AU - McCray, Andrew D.

AU - Cho, Alex

AU - Rockouski, Mary

AU - Orton, Gemma

AU - Goldsmith, Lily

AU - Aronno, Md Mubtaseem Ahnaf

AU - Spencer, Zachary T.

AU - Khan, Omar M.

AU - Ye, Fei

AU - Williams, Charles

AU - Lebensohn, Andres M.

AU - Rohatgi, Rajat

AU - Wang, Xiaofeng

AU - Weiss, Vivian L.

AU - Hong, Charles C.

AU - Kettenbach, Arminja N.

AU - Robbins, David J.

AU - Ahmed, Yashi

AU - Lee, Ethan

PY - 2025/6/5

Y1 - 2025/6/5

N2 - 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.

AB - 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.

KW - Beta-catenin

KW - Cancer

KW - Chromatin remodeling complexes

KW - Drosophila

KW - Genes

KW - Long-range action

KW - Receptor

KW - Transcription factor

KW - Ubiquitin ligase

KW - Zebrafish

UR - https://www.scopus.com/pages/publications/105007522265

U2 - 10.1038/s41467-025-60535-5

DO - 10.1038/s41467-025-60535-5

M3 - Article

AN - SCOPUS:105007522265

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5248

ER -

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

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