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A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions [RNA-seq]

ABSTRACT: RNA is an essential component of the chromatin, influencing genome organization and expression. To investigate the role of lncRNAs in epigenetic activation, we profiled the RNA interactome of SWI/SNF complexes in proliferating and senescent conditions, when cells undergo widespread chromatin rearrangements. The isolation of transcripts associated to SMARCB1 core subunit, together with its chromatin binding profiling, showed prevalent association to active regions where it differentially binds ncRNAs locally transcribed. Among them, LINC00565 interacts with SMARCB1 exclusively in proliferating conditions, exerting a pro-oncogenic role in tumors with intact SWI/SNF complexes. LINC00565 is transcribed from an enhancer region and through binding to SMARCB1, controls the activation of GAS6 oncogene as part of a topologically organized region, as well the activation of a larger set of genes by favoring SMARCB1 binding. Our results indicate that LINC00565 influences the ability of the SWI/SNF complexes to drive epigenetic activation of specific promoters, suggesting a SWI/SNF-RNA cooperation to achieve transcriptional activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128326 | GEO | 2019/12/30

REPOSITORIES: GEO

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A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions [ChIP-Seq]

Project description:RNA is an essential component of the chromatin, influencing genome organization and expression. To investigate the role of lncRNAs in epigenetic activation, we profiled the RNA interactome of SWI/SNF complexes in proliferating and senescent conditions, when cells undergo widespread chromatin rearrangements. The isolation of transcripts associated to SMARCB1 core subunit, together with its chromatin binding profiling, showed prevalent association to active regions where it differentially binds ncRNAs locally transcribed. Among them, LINC00565 interacts with SMARCB1 exclusively in proliferating conditions, exerting a pro-oncogenic role in tumors with intact SWI/SNF complexes. LINC00565 is transcribed from an enhancer region and through binding to SMARCB1, controls the activation of GAS6 oncogene as part of a topologically organized region, as well the activation of a larger set of genes by favoring SMARCB1 binding. Our results indicate that LINC00565 influences the ability of the SWI/SNF complexes to drive epigenetic activation of specific promoters, suggesting a SWI/SNF-RNA cooperation to achieve transcriptional activation.

2019-12-30 | GSE131711 | GEO

A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions [RIP-seq]

2019-12-30 | GSE128139 | GEO

A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers

Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes.

2024-01-21 | PXD046276 | Pride

A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers

2024-01-21 | PXD046273 | Pride

A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers

2024-01-21 | PXD046275 | Pride

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

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

2023-07-14 | GSE210632 | GEO

BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq 2]

Project description:Bromodomain-containing protein 9 (BRD9) was recently identified to be associated with the chromatin remodeling SWI/SNF(BAF) complex, yet its function within the complex has remained unclear. Here, using genome-scale CRISPR-Cas9 screens, we found that BRD9 constitutes a specific vulnerability in highly malignant pediatric rhabdoid tumors, which are driven by inactivating mutations of SMARCB1 subunit of SWI/SNF complexes. Surprisingly, we found that BRD9 does not belong to the previously identified BAF or PBAF complexes, but instead is found exclusively in a novel of SWI/SNF sub-complex. We show that BRD9-containing complexes lack SMARCB1, which had previously been considered a core subunit present in all SWI/SNF variants. We recently demonstrated that both SMARCB1-containing and ARID1A-containing SWI/SNF complexes preferentially function at enhancers, but here we show that BRD9-containing complexes are located at active promoters as well as enhancers. We show that loss of SMARCB1, as observed in rhabdoid tumors, results in increased BRD9 interaction with SWI/SNF core subunit SMARCC1, consistent with competition between SMARCB1 and BRD9 in the formation of SWI/SNF complexes. Underlying the dependency, we demonstrate that BRD9, via its DUF3512 domain, is essential for maintaining the integrity of its sub-complex, which predominates in the absence of SMARCB1. Taken together, our results reveal a BRD9-containing SWI/SNF subcomplex which is required for the survival of SMARCB1-mutant rhabdoid tumors.

2019-03-14 | GSE125775 | GEO

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