BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors

Xiaofeng Wang, Su Wang, Emma C. Troisi, Thomas P. Howard, Jeffrey R. Haswell, Bennett K. Wolf, William H. Hawk, Pilar Ramos, Elaine M. Oberlick, Evgeni P. Tzvetkov, Aaron Ross, Francisca Vazquez, William C. Hahn, Peter J. Park () and Charles W. M. Roberts ()
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Xiaofeng Wang: Dartmouth College
Su Wang: Harvard Medical School
Emma C. Troisi: Dana-Farber Cancer Institute
Thomas P. Howard: Dana-Farber Cancer Institute
Jeffrey R. Haswell: Dana-Farber Cancer Institute
Bennett K. Wolf: Dartmouth College
William H. Hawk: Dartmouth College
Pilar Ramos: St. Jude Children’s Research Hospital
Elaine M. Oberlick: Dana-Farber Cancer Institute
Evgeni P. Tzvetkov: Dana-Farber Cancer Institute
Aaron Ross: St. Jude Children’s Research Hospital
Francisca Vazquez: Broad Institute of Harvard and MIT
William C. Hahn: Broad Institute of Harvard and MIT
Peter J. Park: Harvard Medical School
Charles W. M. Roberts: Dana-Farber Cancer Institute

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Bromodomain-containing protein 9 (BRD9) is a recently identified subunit of SWI/SNF(BAF) chromatin remodeling complexes, yet its function is poorly understood. Here, using a genome-wide CRISPR-Cas9 screen, we show that BRD9 is a specific vulnerability in pediatric malignant rhabdoid tumors (RTs), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF. We find that BRD9 exists in a unique SWI/SNF sub-complex that lacks SMARCB1, which has been considered a core subunit. While SMARCB1-containing SWI/SNF complexes are bound preferentially at enhancers, we show that BRD9-containing complexes exist at both promoters and enhancers. Mechanistically, we show that SMARCB1 loss causes increased BRD9 incorporation into SWI/SNF thus providing insight into BRD9 vulnerability in RTs. Underlying the dependency, while its bromodomain is dispensable, the DUF3512 domain of BRD9 is essential for SWI/SNF integrity in the absence of SMARCB1. Collectively, our results reveal a BRD9-containing SWI/SNF subcomplex is required for the survival of SMARCB1-mutant RTs.

Date: 2019
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DOI: 10.1038/s41467-019-09891-7

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