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

Author

Listed:
  • Xiaofeng Wang

    (Dartmouth College
    Dana-Farber Cancer Institute)

  • Su Wang

    (Harvard Medical School)

  • Emma C. Troisi

    (Dana-Farber Cancer Institute)

  • Thomas P. Howard

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and MIT)

  • 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
    Dana-Farber Cancer Institute)

  • Peter J. Park

    (Harvard Medical School)

  • Charles W. M. Roberts

    (Dana-Farber Cancer Institute
    St. Jude Children’s Research Hospital)

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.

Suggested Citation

  • 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 Va, 2019. "BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09891-7
    DOI: 10.1038/s41467-019-09891-7
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