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| Status |
Public on Mar 11, 2019 |
| Title |
The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Perturbations to mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events across cancers1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits, which has recently been implicated in rare cancers such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. The consequences of SMARCA4/2 dual loss on the biochemical composition of the complex, chromatin targeting and remodeling capabilities, and subcomplex identity (BAF vs. PBAF) in these cancers are unknown. Here, we leverage SCCOHT cell lines to identify an unexpected ATPase module of mSWI/SNF subunits. Using biochemical and genome-wide profiling assays, we found that the incorporation of the ATPase module is a critical step in the functional specification of BAF and PBAF subcomplexes. Furthermore, by utilizing ATPase mutant variants, we found that the ATPase module mediates two separate and concurrent mSWI/SNF targeting mechanisms, evenly split between catalytically-independent targeting to primed enhancers/promoters and catalytically-dependent targeting to de novo enhancers. Finally, by linking these distinct sites to separate tumor-suppressive gene expression programs across ovarian tissues , we clarify the mechanistic consequences of SMARCA4/2 loss dual loss in these rare tumors.
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| Overall design |
SMARCA4/2 deficient BIN-67 cells were treated to overexpress WT and mutant versions of the SMARCA4 ATPase subunit of the mSWI/SNF complex.
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| Contributor(s) |
Pan J, McKenzie Z, D'Avino D, Kadoch C |
| Citation(s) |
30858614 |
| |
| Submission date |
Jul 18, 2018 |
| Last update date |
Jun 10, 2019 |
| Contact name |
Cigall Kadoch |
| Organization name |
Dana Farber Cancer Institute
|
| Department |
Pediatric Oncology
|
| Lab |
Kadoch Lab
|
| Street address |
450 Brookline Avenue
|
| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (11)
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| This SubSeries is part of SuperSeries: |
| GSE117735 |
The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targeting |
|
| Relations |
| BioProject |
PRJNA481742 |
| SRA |
SRP154344 |
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