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

  • Nat Commun. 2019 Apr 23;10(1):1881. doi: 10.1038/s41467-019-09891-7.
Xiaofeng Wang  1  2 ,  Su Wang  3 ,  Emma C Troisi  2 ,  Thomas P Howard  2  4 ,  Jeffrey R Haswell  2 ,  Bennett K Wolf  1 ,  William H Hawk  1 ,  Pilar Ramos  5 ,  Elaine M Oberlick  2 ,  Evgeni P Tzvetkov  2 ,  Aaron Ross  5 ,  Francisca Vazquez  4 ,  William C Hahn  4  6 ,  Peter J Park  7 ,  Charles W M Roberts  8  9
Affiliations
  • 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. [email protected].
  • 8. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. [email protected].
  • 9. Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. [email protected].
PMID: 31015438 DOI: 10.1038/s41467-019-09891-7
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.