Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A non-canonical SWI/SNF complex underlies synthetic lethality in cancers driven by BAF complex perturbation [ChIP-seq]

ABSTRACT: Mammalian SWI/SNF chromatin remodeling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF, and a newly characterized non-canonical complex, ncBAF. However, their complex-specific targeting on chromatin, functions and roles in disease remain largely unknown. Here, we comprehensively map complex assemblies on chromatin and find that ncBAF uniquely localizes to CTCF sites and promoters. We identified ncBAF subunits as major synthetic lethalities specific to human synovial sarcoma and malignant rhabdoid tumor, which share in common cBAF complex perturbation. Chemical degradation of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation. Notably, in cBAF-perturbed cancers, ncBAF complexes retain their hallmark localization to CTCF sites and promoters, and maintain gene expression at retained mSWI/SNF sites to support cell proliferation in a manner distinct from fusion oncoprotein-mediated targeting. Taken together, these findings unmask the unique targeting and function of ncBAF complexes and present new cancer-specific therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113040 | GEO | 2018/11/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A non-canonical SWI/SNF complex underlies synthetic lethality in cancers driven by BAF complex perturbation

Project description:Mammalian SWI/SNF chromatin remodeling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF, and a newly characterized non-canonical complex, ncBAF. However, their complex-specific targeting on chromatin, functions and roles in disease remain largely unknown. Here, we comprehensively map complex assemblies on chromatin and find that ncBAF uniquely localizes to CTCF sites and promoters. We identified ncBAF subunits as major synthetic lethalities specific to human synovial sarcoma and malignant rhabdoid tumor, which share in common cBAF complex perturbation. Chemical and biological depletion of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation. Notably, in cBAF-perturbed cancers, ncBAF complexes retain localization to CTCF sites and promoters, and maintain gene expression at retained mSWI/SNF sites to support cell proliferation in a manner distinct from fusion oncoprotein-mediated targeting. Taken together, these findings unmask the unique targeting and function of ncBAF complexes and present new cancer-specific therapeutic targets.

2018-11-06 | PXD011103 | Pride

A non-canonical SWI/SNF complex underlies synthetic lethality in cancers driven by BAF complex perturbation [RNA-seq]

Project description:Mammalian SWI/SNF chromatin remodeling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF, and a newly characterized non-canonical complex, ncBAF. However, their complex-specific targeting on chromatin, functions and roles in disease remain largely unknown. Here, we comprehensively map complex assemblies on chromatin and find that ncBAF uniquely localizes to CTCF sites and promoters. We identified ncBAF subunits as major synthetic lethalities specific to human synovial sarcoma and malignant rhabdoid tumor, which share in common cBAF complex perturbation. Chemical degradation of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation. Notably, in cBAF-perturbed cancers, ncBAF complexes retain their hallmark localization to CTCF sites and promoters, and maintain gene expression at retained mSWI/SNF sites to support cell proliferation in a manner distinct from fusion oncoprotein-mediated targeting. Taken together, these findings unmask the unique targeting and function of ncBAF complexes and present new cancer-specific therapeutic targets.

2018-11-04 | GSE113041 | GEO

Cancer-specific deficiency of SMARCE1, a module-linking subunit, generates a targetable chromatin regulatory dependency in clear cell meningioma

Project description:Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are critical for establishing and maintaining chromatin accessibility and gene expression and are frequently perturbed in human disease. Select rare cancer types are characterized uniformly by mSWI/SNF subunit perturbations, underscoring their driving roles. Clear cell meningioma (CCM), an aggressive CNS tumor, is driven by loss of the SMARCE1 subunit, found in ~100% of cases. Here we identify an unexpected and evolutionarily conserved structural role for SMARCE1 in selectively stabilizing the cBAF complex core -ATPase module interaction. SMARCE1 is required for stable docking of cBAF complexes to nucleosomes via ATPase rigidification. In CCM, cBAF complexes selectively fail to stabilize on nucleosome substrates and chromatin and residual cores increase the formation of BRD9-containing ncBAF complexes. Combined attenuation of cBAF complex function and ncBAF complex activity generate the CCM-specific gene expression profile, which is distinct from NF2 loss. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small molecule inhibition of ncBAF complexes. These data inform on the function of a previously elusive subunit and suggest new therapeutic approaches for highly aggressive SMARCE1-deficient CCM.

2022-06-16 | GSE174360 | GEO

Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation and genomic profiling

Project description:Mammalian SWI/SNF (mSWI/SNF or BAF) chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression and are comprised of three final-form assemblies, cBAF, PBAF, and ncBAF, which exhibit distinct modular organization, chromatin targeting, and roles in disease. However, the contributions of each subcomplex and their constituent subunits to gene expression remain incompletely defined. Here, we performed a large-scale CRISPR-Cas9 knockout screen targeting mSWI/SNF subunits individually and in selected combinations, followed by single-cell RNA-sequencing (Perturb-seq) and SHARE-Seq. We uncover complex- and module-specific contributions across cell regulatory pathways, define paralog subunit relationships, and identify shifted functions upon perturbations. Finally, we superimpose single-cell perturbation signatures over bulk primary human tumor gene expression profiles, defining unique subunit-specific signatures and identifying tumor features that mirror BAF loss-of-function. Taken together, these data highlight the utility of large-scale single-cell genomics to uncover gene expression and chromatin accessibility signatures in human disease states.

2023-04-05 | GSE200201 | GEO

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers [ATAC-seq]

Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.

2023-07-14 | GSE210632 | GEO

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers [RNA-seq]

2023-07-14 | GSE210635 | GEO

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers [CUT & RUN]

2023-07-14 | GSE210634 | GEO

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers [ChIP-seq]

2023-07-14 | GSE210633 | GEO

Genome-wide maps of SWI/SNF complexes binding in WT and ARID1-less H2.35 cells

Project description:Globally, the three categories of intact SWI/SNF complexes in control cells have shared and unique binding peaks, with cBAF showing the most abundant binding sites followed by ncBAF and pBAF. In control cells, within cBAF, ARID1B bound to only a subset of ARID1A peaks. In control cells, the binding pattern of BAF45d corresponded to ARID1A patterns, but binding was virtually eliminated in ARID1-less cells. In ARID1-less cells, ARID2 binding was essentially eliminated whereas Brd9 binding was unaltered.

2020-06-10 | GSE140183 | GEO

SWI/SNF localization during macrophage inflammatory response [ChIP-seq_SWISNF]

Project description:To understand how the SWI/SNF complex help establish appropriate epiegentic landscape during macrophage inflammatory response, we profiled the binding sites of BRG1 (all BAF), ARID1A (cBAF), BRD9 (ncBAF), and PHF10 (PBAF) for WT BMDMs with 0hr, 1hr, or 4hr LipidA stimulation. To assess the modes of action for cBAF inhibitor BRDK98, we also performed ARID1A ChIP for BRDK98-treated BDMDs after 0hr and 4hr of LipidA stimulation.

2024-06-05 | GSE242801 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data