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) |
|---|---|
| Journal | Nature Genetics |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Genetics
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The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity–independent genomic targeting. / Pan, Joshua; McKenzie, Zachary M.; D’Avino, Andrew R.; Mashtalir, Nazar; Lareau, Caleb A.; St. Pierre, Roodolph; Wang, Lu; Shilatifard, Ali; Kadoch, Cigall.
In: Nature Genetics, 01.01.2019.Research output: Contribution to journal › Letter
TY - JOUR
T1 - The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity–independent genomic targeting
AU - Pan, Joshua
AU - McKenzie, Zachary M.
AU - D’Avino, Andrew R.
AU - Mashtalir, Nazar
AU - Lareau, Caleb A.
AU - St. Pierre, Roodolph
AU - Wang, Lu
AU - Shilatifard, Ali
AU - Kadoch, Cigall
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062883837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062883837&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0363-5
DO - 10.1038/s41588-019-0363-5
M3 - Letter
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
ER -