RNA-seq of HS-SY-II synovial sarcoma cells treated with the BRD9 PROTAC degrader WA-68 across a time course
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE328412 | GEO | 2026/06/24
REPOSITORIES: GEO
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Project description:Synovial sarcoma (SyS) is driven by the SS18::SSX fusion oncoprotein, which incorporates into GBAF chromatin remodeling complexes and creates a dependency on BRD9. To investigate the effects of BRD9 loss, we performed ChIP-seq, ATAC-seq, and RNA-seq in SyS models following BRD9 degradation. ChIP-seq shows reduced GBAF occupancy at target loci, while ATAC-seq reveals maintained or increased chromatin accessibility. RNA-seq demonstrates sustained or elevated expression of target genes. These results indicate that BRD9 is not required for GBAF assembly but instead restrains its remodeling activity, providing a mechanistic explanation for the limited efficacy of BRD9-targeted therapies in SyS.
2026-06-24 | GSE328411 | GEO
Project description:Synovial sarcoma (SyS) is driven by the SS18::SSX fusion oncoprotein, which incorporates into GBAF chromatin remodeling complexes and creates a dependency on BRD9. To investigate the effects of BRD9 loss, we performed ChIP-seq, ATAC-seq, and RNA-seq in SyS models following BRD9 degradation. ChIP-seq shows reduced GBAF occupancy at target loci, while ATAC-seq reveals maintained or increased chromatin accessibility. RNA-seq demonstrates sustained or elevated expression of target genes. These results indicate that BRD9 is not required for GBAF assembly but instead restrains its remodeling activity, providing a mechanistic explanation for the limited efficacy of BRD9-targeted therapies in SyS.
2026-06-24 | GSE328410 | GEO
Project description:In order to evaluate SS18::SSX distribution across chromatin in synovial sarcoma, we performed ChIP-seq from mouse SyS tumors expressing the human SS18::SSX2 using an antibody specific for the fusion oncoprotein SS18::SS. ChIP-seq was also employed to assess SyS genome profiles of specific chromatin histone marks (H2AK119ub, H3K4me1, H3K4me3, H3K27ac and H3K27me3), and chromatin conformation by HiChIP was evaluated using an antibody against H3K27ac to identify enhancer loops for the purpose of assigning distal regulatory elements to specific genes. Furthermore, we also characterize the distribution of each BAF family subtypes with ChIP-seq ( ARID1A (cBAF), DPF2 (cBAF), PBRM1 (PBAF) and BRD9 (GBAF/non-canonical BAF)). In this study, our fundings suggest that SS18::SSX distributes to proximal and distal regulatory elements bearing ubiquitylated histone 2A and GBAF distributes with the fusion to broad proximal and distal regions; CBAF and PBAF distribute narrowly to active transcriptional start sites.
2025-06-10 | GSE269770 | GEO
Project description:H3K27ac is known to associate with regulatory active enhancers, but it’s exact role in enhancer function remains elusive. Using mass spectrometry-based interaction proteomics, we identified the Super Elongation Complex (SEC) and GBAF, a non-canonical GLTSCR1L- and BRD9-containing SWI/SNF chromatin remodeling complex, to be major interactors of H3K27ac. Our interaction proteomics analysis refined the composition of GBAF by adding BCL7A/B/C as a new subunit. We further characterized the conserved GLTSCR1/1L-contained “GiBAF”-domain, which we found to be responsible for GBAF complex formation and nuclear localization. Inhibition of the bromodomain of BRD9 revealed interaction between GLTSCR1L and BRD9 to be H3K27ac dependent and led to GLTSCR1L dislocation from its preferred binding sites at H3K27ac-associated enhancers. GLTSCR1L disassociation from chromatin resulted in a genome-wide downregulation of enhancer transcription. Our results indicate that GBAF is an enhancer-associated chromatin remodeller important for the correct transcriptional and regulatory activity of enhancers.
2018-10-17 | GSE121351 | GEO
Project description:The mammalian BRG1-associated factors (BAF) complex is a multi-subunit chromatin remodeling complex that is an important component of the embryonic stem cell (ESC) transcriptional regulatory network. However, the role of individual subunits in BAF complex targeting and function needs to be elucidated. Here, we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1; also known as BICRA) or its paralog GLTSCR1-like (also known as BICRAL) define a smaller, non-canonical BAF complex (GBAF for GLTSCR1/1L-containing BAF complex) in mouse ESCs that is distinct from the canonical embryonic stem cell BAF (esBAF) and the polybromo-associated BAF (PBAF) complexes. GBAF lacks several esBAF subunits, including BAF47, BAF57 and ARID1A. We demonstrate that GBAF and esBAF complexes are targeted to different features of the genome and are co-bound with different sets of pluripotency transcription factors. Specifically, GBAF complexes co-localize with key regulators of naïve pluripotency, KLF4 and Sp5, on the genome. Consistent with this, we provide evidence that GBAF's specific function is to regulate the transcription of genes involved in the maintenance of naïve pluripotency, including Nanog and Prdm14. Additionally, we show that BRD9 is displaced from chromatin by the selective BRD9 bromodomain inhibitor, I-BRD9, and that this leads to changes in target gene expression. The function of the GBAF complex in ESCs is highly correlated with the function of BRD4, consistent with an association between GBAF complexes and BRD4. We find that GBAF complexes are directly recruited to chromatin by BRD4 in a bromodomain-dependent fashion and we identify a set of I-BRD9- and JQ1-sensitive BRD9 binding sites that determine the functional similarity between these epigenetic regulators. Together, our results demonstrate functionally specific roles for BAF complex assemblies in maintaining the transcriptional network of pluripotency, highlighting the biological importance of complex heterogeneity.
2018-10-19 | GSE111264 | GEO
Project description:Synovial sarcoma (SS) is a rare malignancy, involves a t(X;18) chromosomal translocation that creates a fusion gene SS18-SSX. SS18 is a chromatin remodeling BAF-complexes component, which incorporated in CBAF and GBAF (non-canonical ncBAF). Our previous studies determined that incorporation of the fusion oncoprotein caused degradation of CBAF complexes, emphasizing a critical oncogenic function of GBAF and PBAF in synovial sarcomagenesis. To determine the SyS dependencies on different subtypes of BAF complexes during tumor development in vivo, we used our SyS mouse model combined with genetic disruption of specific BAF complexes components ARID1A/B or PBRM1. In this study, our fundings suggest that depletion of ARID1A and ARID1B sped tumorigenesis, without significant change in the histomorphology of the developing tumors. Loss of PBRM1 also led to faster tumor growing, but Pbrm1-silenced tumors lacked the full array of SyS histomorphologies observed in wildtype tumors. Overall, Arid1a or Arid1b disruption rendered tumor transcriptomes that clustered within the hSS2 tumor transcriptomes, unlike Pbrm1 disrupted tumors.
2025-06-10 | GSE269772 | GEO
Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.
2023-07-14 | GSE210635 | GEO
Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.
2023-07-14 | GSE210634 | GEO
Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.
2023-07-14 | GSE210632 | GEO
Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.
2023-07-14 | GSE210633 | GEO