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Nat Commun. 2019 Apr 23;10(1):1881. doi: 10.1038/s41467-019-09891-7.

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

Author information

1
Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03756, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
3
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
4
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA.
5
Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
7
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA. peter_park@hms.harvard.edu.
8
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. Charles.Roberts@STJUDE.ORG.
9
Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Charles.Roberts@STJUDE.ORG.

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.

PMID:
31015438
PMCID:
PMC6479050
DOI:
10.1038/s41467-019-09891-7
[Indexed for MEDLINE]
Free PMC Article

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