The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA813879 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18272176_1.fastq.gz | Fastqsanger.gz | |||
| SRR18272176_2.fastq.gz | Fastqsanger.gz | |||
| SRR18272177_1.fastq.gz | Fastqsanger.gz | |||
| SRR18272177_2.fastq.gz | Fastqsanger.gz | |||
| SRR18272178_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1—which becomes essential in the absence of SMARCB1—but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as critical downstream effector of pro-tumorigenic transcriptional programs.
2024-02-23 | GSE241874 | GEO
Project description:Here, we expose the connection between rSWI/SNF and oncogenic processes using a well-characterized chemical degrader to deplete the SWI/SNF ATPase, BRG1. Using a combination of gene expression and chromatin accessibility assays we show that rSWI/SNF complexes facilitate MYC target gene expression. We also find that rSWI/SNF maintains open chromatin at sites associated with hallmark cancer genes linked to the AP-1 transcription factor, suggesting that AP-1 may drive oncogenesis in MRT.
2022-05-31 | GSE198156 | GEO
Project description:DOX-dependently SMARCB1-re-expressing, stable isogenic EpS cell line models were generated and submitted to global proteomic analysis as well as interactome analysis by co-immunoprecipitation of BRG1, one of the SWI/SNF core ATPases after 96h of DOX treatment.
2024-12-17 | PXD053945 | Pride
Project description:Malignant rhabdoid tumor (MRT) is driven by the loss of the SNF5 subunit of the SWI/SNF chromatin remodeling complex and then thought to be maintained by residual SWI/SNF (rSWI/SNF) complexes that remain present in the absence of SNF5. rSWI/SNF subunits colocalize extensively on chromatin with the transcription factor MYC, an oncogene identified as a novel driver of MRT. Currently, the role of rSWI/SNF in modulating MYC activity has neither been delineated nor has a direct link between rSWI/SNF and other oncogenes been uncovered. Here, we expose the connection between rSWI/SNF and oncogenic processes using a well-characterized chemical degrader to deplete the SWI/SNF ATPase, BRG1. Using a combination of gene expression and chromatin accessibility assays we show that rSWI/SNF complexes facilitate MYC target gene expression. We also find that rSWI/SNF maintains open chromatin at sites associated with hallmark cancer genes linked to the AP-1 transcription factor, suggesting that AP-1 may drive oncogenesis in MRT. Interestingly, changes in MYC target gene expression are not overtly connected to the chromatin remodeling function of rSWI/SNF, revealing multiple mechanisms used by rSWI/SNF to control transcription. This work provides an understanding of how residual SWI/SNF complexes may converge on multiple oncogenic processes when normal SWI/SNF function is impaired.
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Project description:The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the ATPase subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression, however aberrant remodeling and gene expression can result in cancer. The function and localization on chromatin of the SWI/SNF complex depends on the protein makeup of the complex. Here we report the protein-protein interactions of wild-type BRG1 or mutant BRG1 in which the HSA domain has been deleted (BRG1-HSA). We demonstrate the interaction of BRG1 with most SWI/SNF complex members and a failure of a number of these members to interact with BRG1-HSA. These results demonstrate that the HSA domain of BRG1 is a critical interaction platform for the correct formation of SWI/SNF remodeling complexes.
2023-02-15 | PXD029647 | Pride
Project description:Inositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events, including transcriptional control. In the yeast, IPMK and its IP products promote the activity of the chromatin-remodeling complex SWI/SNF, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct link between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screening approaches and in vivo/in vitro immunoprecipitations, here we demonstrated that mammalian IPMK physically interacts with the SWI/SNF complex by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using the CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate the expression of a common gene set, validating a functional link between IPMK and the SWI/SNF complex. Together, these findings show that IPMK regulates promoter-targeting of the SWI/SNF complex and thereby contributes to SWI/SNF-meditated chromatin accessibility, transcription, and differentiation.
2022-05-10 | GSE158525 | GEO
Project description:We exogenously expressed the SWI/SNF ATPase catalytic subunits BRG1 and BRM in the lacking cell line C33A, and compared the differences with mock transfected cell at gene expression and alternative splicing level.
2022-03-17 | GSE140474 | GEO
Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and presents a conundrum for precision therapy because the proteins are no longer present. SMARCB1-mutant cancers epitomize this challenge because these highly lethal cancers are driven by inactivation of a single gene, a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to seek vulnerabilities, we contributed 16 SMARCB1-mutant cell lines to a near-genomewide CRISPR screen as part of the Cancer Dependency Map1-3. Here we report that the little-studied gene DCAF5 (DDB1-CUL4 Associated Factor 5) is a specific dependency in SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and in the absence of SMARCB1 DCAF5 causes degradation of incompletely assembled SWI/SNF complexes. Upon inhibition of DCAF5 SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore gene expression to levels sufficient to fully reverse the cancer state, including in a xenograft mouse model. 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 DCAF5 may be sufficient to restore substantial SWI/SNF function and reverse cancer phenotypes caused by SMARCB1 loss.
2024-03-22 | GSE215023 | GEO
Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and presents a conundrum for precision therapy because the proteins are no longer present. SMARCB1-mutant cancers epitomize this challenge because these highly lethal cancers are driven by inactivation of a single gene, a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to seek vulnerabilities, we contributed 16 SMARCB1-mutant cell lines to a near-genomewide CRISPR screen as part of the Cancer Dependency Map1-3. Here we report that the little-studied gene DCAF5 (DDB1-CUL4 Associated Factor 5) is a specific dependency in SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and in the absence of SMARCB1 DCAF5 causes degradation of incompletely assembled SWI/SNF complexes. Upon inhibition of DCAF5 SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore gene expression to levels sufficient to fully reverse the cancer state, including in a xenograft mouse model. 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 DCAF5 may be sufficient to restore substantial SWI/SNF function and reverse cancer phenotypes caused by SMARCB1 loss.
2024-03-22 | GSE215022 | GEO
Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and presents a conundrum for precision therapy because the proteins are no longer present. SMARCB1-mutant cancers epitomize this challenge because these highly lethal cancers are driven by inactivation of a single gene, a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to seek vulnerabilities, we contributed 16 SMARCB1-mutant cell lines to a near-genomewide CRISPR screen as part of the Cancer Dependency Map1-3. Here we report that the little-studied gene DCAF5 (DDB1-CUL4 Associated Factor 5) is a specific dependency in SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and in the absence of SMARCB1 DCAF5 causes degradation of incompletely assembled SWI/SNF complexes. Upon inhibition of DCAF5 SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore gene expression to levels sufficient to fully reverse the cancer state, including in a xenograft mouse model. 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 DCAF5 may be sufficient to restore substantial SWI/SNF function and reverse cancer phenotypes caused by SMARCB1 loss.
2024-03-22 | GSE215024 | GEO