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Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas [ATAC/ChIP/RNA]

ABSTRACT: Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas [ATAC/ChIP/RNA]

PROVIDER: PRJNA1195678 | ENA |

REPOSITORIES: ENA

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Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas

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

Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas

Project description:Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas

| PRJNA1119509 | ENA

Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas [ATAC/ChIP/RNA]

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Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-08-04 | GSE268960 | GEO

Non-Canonical BAF and mSWI/SNF Regulates POU2F3 and are Selective Targetable Dependencies for POU2F3-Positive Small Cell Lung Cancer

Project description:Non-Canonical BAF and mSWI/SNF Regulates POU2F3 and are Selective Targetable Dependencies for POU2F3-Positive Small Cell Lung Cancer

| PRJNA1048875 | ENA

Non-Canonical BAF and mSWI/SNF Regulates POU2F3 and are Selective Targetable Dependencies for POU2F3-Positive Small Cell Lung Cancer

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.

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Precise modulation of mSWI/SNF identified dosage-sensitive chromatin regulation [CUT&Run]

Project description:ATP-dependent chromatin remodelers establish and arrange nucleosome distribution, modifying accessibility of DNA. Brg1 is exclusive ATPase subunit of mSWI/SNF complex. To understand the dosage dependent function of mSWI/SNF complex. We take an advantage of dTag system to precisely control abundancy of BRG1. We found overall Brg1-binding is sensitive to its abundance nevertheless OCT4-target or H3K27ac region, suggesting Brg1 genome-wide distribution rather than being actively recruited. We also reveal open chromatin dependency on BRG1. The chromatin accessibility of super enhancer shows buffered response on depletion of BRG1, whereas weak enhancer is sensitive. Finally, transcriptomic analysis identified that transcription shows buffered dependencies on BRG1 loss. Overall, our results highlight kinetics differences of BRG1-binding to transcriptome underline BRG1 dosage-sensitive mechanism.

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