Abstract
Perturbations to mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events in cancer 1 . One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) 2–5 , SMARCA4-deficient thoracic sarcomas 6 and dedifferentiated endometrial carcinomas 7 . However, the consequences of dual ATPase subunit loss on mSWI/SNF complex subunit composition, chromatin targeting, DNA accessibility and gene expression remain unknown. Here we identify an ATPase module of subunits that is required for functional specification of the Brahma-related gene–associated factor (BAF) and polybromo-associated BAF (PBAF) mSWI/SNF family subcomplexes. Using SMARCA4/2 ATPase mutant variants, we define the catalytic activity–dependent and catalytic activity–independent contributions of the ATPase module to the targeting of BAF and PBAF complexes on chromatin genome-wide. Finally, by linking distinct mSWI/SNF complex target sites to tumor-suppressive gene expression programs, we clarify the transcriptional consequences of SMARCA4/2 dual loss in SCCOHT.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 618-626 |
| Number of pages | 9 |
| Journal | Nature Genetics |
| Volume | 51 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2019 |
Funding
We thank members of the Kadoch Laboratory for helpful conceptual and experimental advice throughout the development of this study. We thank the DFCI Molecular Biology Core Facility, particularly Z. Herbert, for library preparation and sequencing, G. Boulay for advice regarding ChIP-seq optimization and the Taplin Mass Spectrometry Facility for mass-spectrometry analysis and data processing. We thank B. Vanderhyden (Ottawa Hospital Research Institute) and R. Hass (Hannover Medical School) for providing the BIN-67 and SCCOHT-1 cell lines, respectively. This work was supported in part by funding from the National Science Foundation Graduate Research Fellowship (No. 2015185722) and NIH T32 Training Grant in Genetics and Genomics to J.P.; the NIH DP2 New Innovator Award (No. 1DP2CA195762-01) to C.K.; the American Cancer Society Research Scholar Award (No. RSG-14-051-01-DMC) to C.K.; and the Pew–Stewart Scholars in Cancer Research Grant to C.K.
ASJC Scopus subject areas
- Genetics
