Similar Datasets
Project description:ARID2 is an essential subunit of the SWI/SNF PBAF chromatin remodeler and is highly mutate in melanoma. To elucidate the role of ARID2 in melanoma biology and chromatin structure we utilized CRISPR Cas9 methodology to generate isogenic ARID2 WT and KO melanoma clonal cell lines. We further map the genomic localization of several SWI/SNF subunits, open and repressed chromatin markers, and multiple transcription factors to characterize how loss of the PBAF subcomplex alters chromatin accessibility and the melanoma transcription factor network. Finally, we characterized the transcriptional changes produced by PBAF depletion.
2022-04-05 | GSE172383 | GEO
Project description:ARID2 is the most recurrently mutated SWI/SNF complex member in melanoma; however, its tumor-suppressive mechanisms in the context of the chromatin landscape remain to be elucidated. Here, we model ARID2 deficiency in melanoma cells, which results in defective PBAF complex assembly with a concomitant genomic redistribution of the BAF complex. Upon ARID2 depletion, a subset of PBAF and shared BAF-PBAF-occupied regions displays diminished chromatin accessibility and associated gene expression, while BAF-occupied enhancers gain chromatin accessibility and expression of genes linked to the process of invasion. As a function of altered accessibility, the genomic occupancy of melanoma-relevant transcription factors is affected and significantly correlates with the observed transcriptional changes. We further demonstrate that ARID2-deficient cells acquire the ability to colonize distal organs in multiple animal models. Taken together, our results reveal a role for ARID2 in mediating BAF and PBAF subcomplex chromatin dynamics with consequences for melanoma metastasis.
| S-EPMC9013128 | biostudies-literature
Project description:ARID2 is an essential subunit of the SWI/SNF PBAF chromatin remodeler and is highly mutate in melanoma. To elucidate the role of ARID2 in melanoma biology and chromatin structure we utilized CRISPR Cas9 methodology to generate isogenic ARID2 WT and KO melanoma clonal cell lines. We further map the genomic localization of several SWI/SNF subunits, open and repressed chromatin markers, and multiple transcription factors to characterize how loss of the PBAF subcomplex alters chromatin accessibility and the melanoma transcription factor network. Finally, we characterized the transcriptional changes produced by PBAF depletion.
2022-04-05 | GSE172384 | GEO
Project description:PBAF complex deficiency in melanoma mediates BAF occupancy and transcription factor dynamics
| PRJNA723186 | ENA
Project description:PBAF complex deficiency in melanoma mediates BAF occupancy and transcription factor dynamics (Chromatin)
| PRJNA723190 | ENA
Project description:PBAF complex deficiency in melanoma mediates BAF occupancy and transcription factor dynamics (RNA-Seq)
| PRJNA723192 | ENA
Project description:The PBAF complex, a member of SWI/SNF family of chromatin remodelers, plays an essential role in transcriptional regulation. We revealed a disease progression associated elevation of PHF10 subunit of PBAF in clinical melanoma samples. In melanoma cell lines, PHF10 interacts with MYC and facilitates the recruitment of PBAF complex to target gene promoters, therefore, augmenting MYC transcriptional activation of genes involved in the cell cycle progression. Depletion of either PHF10 or MYC induced G1 accumulation and a senescence-like phenotype. Our data identify PHF10 as a pro-oncogenic mechanism and an essential novel link between chromatin remodeling and MYC-dependent gene transcription.
| S-EPMC8863208 | biostudies-literature
Project description:Alterations of genes encoding subunits of the BAF/PBAF complexes are among the most frequent gene aberrations in human cancer. Such alterations have been shown to have an impact on tumor microenvironnement and on the capacity of tumors to respond to immune-checkpoint inhibitors (ICI). We analysed the clinical and genetic data from 43,728 patients accessed through cBioportal. The mutational frequencies of ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1 were 6.6%, 3,4, 3.4, 3.2, 4.1, and 1.2%, respectively. We then investigated the association between the presence of least one nonsynonymous somatic mutation of ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, or SMARCB1 and overall survival of 1661 patients treated with an ICI. Across the entire cohort, patients with BAF/PBAF mutated tumors have a statistically significant improvement in overall survival (median overall survival: 28 months [95% CI 21.6-34.3] versus 15 months [95% CI 12.9-17.0], p < 0.0001). When tumor mutational burden was adjusted for a multivariable Cox regression analysis, BAF/PBAF gene mutations remained an independent prognostic factor for overall survival in patients treated ICI. Our results establish a relationship between mutations in key genes encoding for components of the BAF/PBAF complex and outcome of patients treated with ICI. Further studies are needed to elucidate the underlying mechanisms of this interaction.
| S-EPMC7366303 | biostudies-literature
Project description:To adapt to stress, cells must undergo major changes in their gene expression profiles. We have previously described a largely uncharacterized stress response pathway in Caenorhabditis elegans that acts through an evolutionarily conserved motif, termed ESRE, for ethanol and stress response element. We characterize here the requirements for ESRE gene expression and show that the ESRE network is regulated by a conserved SWI/SNF family nucleosome remodeling complex termed PBAF. Depletion of PBAF subunits SWSN-7/BAF200 and PBRM-1/BAF180 results in decreased expression of ESRE genes and increased sensitivity to thermal stress. When overexpressed, SWSN-7/BAF200 and PBRM-1/BAF180 led to increased ESRE transcription, enhanced thermotolerance, and induction of a nuclear ESRE-binding activity. Our data support a model in which PBAF is recruited by an ESRE-binding protein to genomic ESRE sites. We also show that the closely related SWI/SNF complex, BAF, which regulates stress induction through DAF-16/FOXO, does not contribute to ESRE gene expression or bind directly to ESRE sites. To our knowledge, this is the first report demonstrating direct and specific regulation of a stress response network by the PBAF nucleosome-remodeling complex in vivo in metazoa. In addition, we show that PBAF cooperates with the histone demethylase, JMJC-1/NO66, to promote expression of ESRE genes following stress.
| S-EPMC3958046 | biostudies-literature
Project description:The Switch/Sugar Non-Fermenting (SWI/SNF) nucleosome remodeling complexes play important roles in normal development and in the development of various cancers. Core subunits of the SWI/SNF complexes have been shown to have oncogenic roles in acute myeloid leukemia. However, the roles of the unique targeting subunits, including that of Arid2 and Arid1b, in AML leukemogenesis are not well understood. Here, we used conditional knockout mouse models to elucidate their role in MLL-AF9 leukemogenesis. We uncovered that Arid2 has dual roles; enhancing leukemogenesis when deleted during leukemia initiation and yet is required during leukemia maintenance. Whereas, deleting Arid1b in either phase promotes leukemogenesis. Our integrated analyses of transcriptomics and genomic binding data showed that, globally, Arid2 and Arid1b regulate largely distinct sets of genes at different disease stages, respectively, and in comparison, to each other. Amongst the most highly dysregulated transcription factors upon their loss, Arid2 and Arid1b converged on the regulation of Etv4/Etv5, albeit in an opposing manner while also regulating distinct TFs including Gata2,Tcf4, Six4, Irf4 and Hmgn3. Our data demonstrate the differential roles of SWI/SNF subunits in AML leukemogenesis and emphasize that cellular context and disease stage are key in determining their functions during this process.
| S-EPMC10095935 | biostudies-literature