Similar Datasets
Project description:The mammalian SWI/SNF (mSWI/SNF) family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BAF (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently dual deleted in highly aggressive differentiated endometrial carcinomas (DECs). Here, in cellular models and primary human tumors, we find that ARID1A/B-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and function genome-wide to maintain the DEC oncogenic signature. Further, treatment of ARID1A/1B-mutant cell lines and PDX models in vivo with a clinical-grade SMARCA4/2 ATPase inhibitor, FHD-286, markedly attenuates cell proliferation and tumor growth, and synergizes with carboplatin-based chemotherapy. Taken together, these findings reveal the oncogenic contributions of shifted of mSWI/SNF family complex abundance and chromatin-level gene regulatory functions and suggest therapeutic utility of mSWI/SNF complex small molecule inhibitors in dedifferentiated endometrial carcinoma and other cBAF-disrupted cancer types.
2025-08-07 | PXD058236 | Pride
Project description:The mammalian SWI/SNF (mSWI/SNF) family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BAF (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently dual deleted in highly aggressive differentiated endometrial carcinomas (DECs). Here, in cellular models and primary human tumors, we find that ARID1A/B-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and function genome-wide to maintain the DEC oncogenic signature. Further, treatment of ARID1A/1B-mutant cell lines and PDX models in vivo with a clinical-grade SMARCA4/2 ATPase inhibitor, FHD-286, markedly attenuates cell proliferation and tumor growth, and synergizes with carboplatin-based chemotherapy. Taken together, these findings reveal the oncogenic contributions of shifted of mSWI/SNF family complex abundance and chromatin-level gene regulatory functions and suggest therapeutic utility of mSWI/SNF complex small molecule inhibitors in dedifferentiated endometrial carcinoma and other cBAF-disrupted cancer types.
2025-08-04 | GSE283800 | GEO
Project description:Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas
| PRJNA1119509 | ENA
Project description:Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas [ATAC/ChIP/RNA]
| PRJNA1195678 | ENA
Project description:Interactions between chromatin-associated proteins and the histone landscape play major roles in dictating genome topology and gene expression. Cancer-specific fusion oncoproteins, which display unique chromatin localization patterns, often lack classical DNA-binding domains, presenting challenges in identifying mechanisms governing their site-specific chromatin targeting and function. Here we identify a minimal region of the human SS18-SSX fusion oncoprotein (the hallmark driver of synovial sarcoma) that mediates a direct interaction between the mSWI/SNF complex and the nucleosome acidic patch. This binding results in altered mSWI/SNF composition and nucleosome engagement, driving cancer-specific mSWI/SNF complex targeting and gene expression. Furthermore, the C-terminal region of SSX confers preferential affinity to repressed, H2AK119Ub-marked nucleosomes, underlying the selective targeting to polycomb-marked genomic regions and synovial sarcoma-specific dependency on PRC1 function. Together, our results describe a functional interplay between a key nucleosome binding hub and a histone modification that underlies the disease-specific recruitment of a major chromatin remodeling complex.
| S-EPMC7714695 | biostudies-literature
Project description:Mammalian SWI/SNF (mSWI/SNF) adenosine triphosphate-dependent chromatin remodelers modulate genomic architecture and gene expression and are frequently mutated in disease. However, the specific chromatin features that govern their nucleosome binding and remodeling activities remain unknown. We subjected endogenously purified mSWI/SNF complexes and their constituent assembly modules to a diverse library of DNA-barcoded mononucleosomes, performing more than 25,000 binding and remodeling measurements. Here, we define histone modification-, variant-, and mutation-specific effects, alone and in combination, on mSWI/SNF activities and chromatin interactions. Further, we identify the combinatorial contributions of complex module components, reader domains, and nucleosome engagement properties to the localization of complexes to selectively permissive chromatin states. These findings uncover principles that shape the genomic binding and activity of a major chromatin remodeler complex family.
| S-EPMC8390793 | biostudies-literature
Project description:Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
| S-EPMC10121856 | biostudies-literature
Project description:~12% of SCLCs are marked by the lineage transcription factor POU2F3, which is essential in all POU2F3-positive SCLCs. Thus, approaches to directly or indirectly inhibit POU2F3 could lead to new therapeutic strategies for POU2F3-positive SCLCs. Here we use a positive selection screening strategy where endogenous POU2F3 is fused to the suicide gene DCK*. Cells that express endogenous POU2F3-DCK* are killed in the presence of the nucleoside analog BVdU and only cells that downregulate the POU2F3-DCK* fusion survive. Genome-wide CRISPR/Cas9 resistance screens with BVdU in POU2F3-DCK* cells uncovered that inactivation of SMARCD1 or BRD9, both components of the non-canonical BAF (ncBAF) complex, markedly downregulate endogenous POU2F3. We find that all POU2F3-positive SCLC cell lines relative to ASCL1-positive and NEUROD1-positive cell lines, are exquisitely sensitive to mSWI/SNF complex inhibition using SMARCA2/4 inhibitors; while pure non-neuroendocrine POU2F3-positive SCLC cell lines are highly sensitive to ncBAF complex inhibition using highly selective BRD9 degraders. Mechanistically, BRD9 binds and regulates POU2F3 target genes including POU2F3 itself. BRD9 degraders or SMARCA2/4 inhibitors robustly decrease accessibility of POU2F3 target genes effectively shutting off POU2F3 function. Moreover, BRD9 degraders or SMARCA2/4 inhibitors decrease tumor growth and increase survival of mice bearing non-neuroendocrine POU2F3 xenografts. This works shows that mSWI/SNF and ncBAF tightly regulate POU2F3 expression and activity and nominate mSWI/SNF or ncBAF inhibition as druggable therapeutic strategies to selectively target POU2F3-positive SCLCs.
2024-06-14 | GSE249362 | GEO
Project description:DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.
| S-EPMC10412456 | biostudies-literature
Project description:Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) complexes, promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and represent host-directed therapeutic targets. The catalytic activity of SMARCA4 is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, ACE2 expression and virus susceptibility. The transcription factors HNF1A/B interact with and recruit mSWI/SNF complexes to ACE2 enhancers, which contain high HNF1A motif density. Notably, small-molecule mSWI/SNF ATPase inhibitors or degraders abrogate angiotensin-converting enzyme 2 (ACE2) expression and confer resistance to SARS-CoV-2 variants and a remdesivir-resistant virus in three cell lines and three primary human cell types, including airway epithelial cells, by up to 5 logs. These data highlight the role of mSWI/SNF complex activities in conferring SARS-CoV-2 susceptibility and identify a potential class of broad-acting antivirals to combat emerging coronaviruses and drug-resistant variants.
| S-EPMC10011139 | biostudies-literature