The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity–independent genomic targeting

Joshua Pan, Zachary M. McKenzie, Andrew R. D’Avino, Nazar Mashtalir, Caleb A. Lareau, Roodolph St. Pierre, Lu Wang, Ali Shilatifard, Cigall Kadoch

Research output: Contribution to journalLetter

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 languageEnglish (US)
JournalNature Genetics
DOIs
StatePublished - Jan 1 2019

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Adenosine Triphosphatases
Sucrose
Small Cell Carcinoma
Chromatin
Ovary
Gene Expression
Chromatin Assembly and Disassembly
Endometrial Neoplasms
Sarcoma
Neoplasms
Thorax
Genome
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

Pan, Joshua ; McKenzie, Zachary M. ; D’Avino, Andrew R. ; Mashtalir, Nazar ; Lareau, Caleb A. ; St. Pierre, Roodolph ; Wang, Lu ; Shilatifard, Ali ; Kadoch, Cigall. / The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity–independent genomic targeting. In: Nature Genetics. 2019.
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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.",
author = "Joshua Pan and McKenzie, {Zachary M.} and D’Avino, {Andrew R.} and Nazar Mashtalir and Lareau, {Caleb A.} and {St. Pierre}, Roodolph and Lu Wang and Ali Shilatifard and Cigall Kadoch",
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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 journalLetter

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.

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