Ontology highlight
ABSTRACT:
PROVIDER: PRJNA507754 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8267300_1.fastq.gz | Fastqsanger.gz | |||
| SRR8267300_2.fastq.gz | Fastqsanger.gz | |||
| SRR8267310_1.fastq.gz | Fastqsanger.gz | |||
| SRR8267310_2.fastq.gz | Fastqsanger.gz | |||
| SRR8267320_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 120 |
Similar Datasets
Project description:Gupta M, Concepcion CP, Fahey CG, Keshishian H, Bhutkar A, Brainson CF, Sanchez-Rivera FJ, Pessina P, Kim JY, Simoneau A, Paschini M, Beytagh MC, Stanclift C, Schenone M, Mani DR, Li C, Oh A, Li F, Hu H, Karatza A, Bronson RT, Shaw AT, Hata AN, Wong K, Zou L, Carr SA, Jacks T, Kim CF. Cancer Res 2020.
Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF
complexes, occurs at very high frequencies in non-small cell lung cancers. There are no
targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1
contribute to lung cancer progression. Using a combination of gain- and loss-of-function
approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of
replication stress responses. Single-molecule assessment of replication fork dynamics in
BRG1-deficient cells revealed increased origin firing, mediated through pre-licensing protein
CDC6. Quantitative mass spectrometry and co-immunoprecipitation assays showed that
BRG1-containing SWI/SNF complexes interact with RPA complexes. Lastly, we show that
BRG1-deficient lung cancers are sensitive to the pharmacological inhibition of ATR. These
findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that
their ATR dependency can be leveraged therapeutically, and potentially expanded to BRG1-
mutant cancers in other tissues.
2020-07-08 | MSV000085701 | MassIVE
Project description:ATP-dependent chromatin remodelers are commonly mutated in human cancer. Mammalian SWI/SNF complexes comprise three conserved multi-subunit chromatin remodelers (cBAF, ncBAF and PBAF) that share the BRG1 (also known as SMARCA4) subunit responsible for the main ATPase activity. BRG1 is the most frequently mutated Snf2-like ATPase in cancer. Here we have investigated the role of SWI/SNF in genome instability, a hallmark of cancer cells, given its role in transcription, DNA replication and DNA damage repair. We show that depletion of BRG1 increases R-loops and R-loop-dependent DNA breaks, as well as transcription-replication conflicts. BRG1 colocalizes with R-loops and replication fork blocks, as determined by FANCD2 foci, with BRG1 depletion being epistatic to FANCD2 silencing. Our study, extended to other components of SWI/SNF, uncovers a key role of the SWI/SNF complex, in particular cBAF, in helping resolve R-loop-mediated transcription-replication conflicts; thus, unveiling a novel mechanism by which chromatin remodeling protects genome integrity.
2021-05-10 | GSE154631 | GEO
Project description:Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, is frequently inactivated in cancers which is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA2/4 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
2019-01-03 | GSE121755 | GEO
Project description:Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance seen in 10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify SWI/SNF subunits that are deregulated in NEPC, demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease and that SMARCA4 depletion impairs prostate cancer cell growth. We also show that SWI/SNF complexes interact with different lineage-specific factors in prostate adenocarcinoma and in NEPC cells, and that induction of lineage plasticity through depletion of REST is accompanied by changes in SWI/SNF genome occupancy. These data suggest a specific role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.
2020-11-04 | PXD016861 | Pride
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:The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
2019-02-10 | GSE110449 | GEO
Project description:The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
2019-02-10 | GSE110448 | GEO
Project description:Perturbations to mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events across cancers1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits, which has recently been implicated in rare cancers such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. The consequences of SMARCA4/2 dual loss on the biochemical composition of the complex, chromatin targeting and remodeling capabilities, and subcomplex identity (BAF vs. PBAF) in these cancers are unknown. Here, we leverage SCCOHT cell lines to identify an unexpected ATPase module of mSWI/SNF subunits. Using biochemical and genome-wide profiling assays, we found that the incorporation of the ATPase module is a critical step in the functional specification of BAF and PBAF subcomplexes. Furthermore, by utilizing ATPase mutant variants, we found that the ATPase module mediates two separate and concurrent mSWI/SNF targeting mechanisms, evenly split between catalytically-independent targeting to primed enhancers/promoters and catalytically-dependent targeting to de novo enhancers. Finally, by linking these distinct sites to separate tumor-suppressive gene expression programs across ovarian tissues , we clarify the mechanistic consequences of SMARCA4/2 loss dual loss in these rare tumors.
2019-03-11 | GSE117311 | GEO
Project description:Perturbations to mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events across cancers1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits, which has recently been implicated in rare cancers such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. The consequences of SMARCA4/2 dual loss on the biochemical composition of the complex, chromatin targeting and remodeling capabilities, and subcomplex identity (BAF vs. PBAF) in these cancers are unknown. Here, we leverage SCCOHT cell lines to identify an unexpected ATPase module of mSWI/SNF subunits. Using biochemical and genome-wide profiling assays, we found that the incorporation of the ATPase module is a critical step in the functional specification of BAF and PBAF subcomplexes. Furthermore, by utilizing ATPase mutant variants, we found that the ATPase module mediates two separate and concurrent mSWI/SNF targeting mechanisms, evenly split between catalytically-independent targeting to primed enhancers/promoters and catalytically-dependent targeting to de novo enhancers. Finally, by linking these distinct sites to separate tumor-suppressive gene expression programs across ovarian tissues , we clarify the mechanistic consequences of SMARCA4/2 loss dual loss in these rare tumors.
2019-03-11 | GSE117301 | GEO
Project description:Perturbations to mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events across cancers1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits, which has recently been implicated in rare cancers such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. The consequences of SMARCA4/2 dual loss on the biochemical composition of the complex, chromatin targeting and remodeling capabilities, and subcomplex identity (BAF vs. PBAF) in these cancers are unknown. Here, we leverage SCCOHT cell lines to identify an unexpected ATPase module of mSWI/SNF subunits. Using biochemical and genome-wide profiling assays, we found that the incorporation of the ATPase module is a critical step in the functional specification of BAF and PBAF subcomplexes. Furthermore, by utilizing ATPase mutant variants, we found that the ATPase module mediates two separate and concurrent mSWI/SNF targeting mechanisms, evenly split between catalytically-independent targeting to primed enhancers/promoters and catalytically-dependent targeting to de novo enhancers. Finally, by linking these distinct sites to separate tumor-suppressive gene expression programs across ovarian tissues , we clarify the mechanistic consequences of SMARCA4/2 loss dual loss in these rare tumors.
2019-03-11 | GSE117734 | GEO