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The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117311 | GEO | 2019/03/11

REPOSITORIES: GEO

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The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [ATAC-seq]

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

The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [ChIP-seq]

2019-03-11 | GSE117734 | GEO

The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [RNA-seq]

Project description:The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [RNA-seq]

| PRJNA481742 | ENA

The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [ATAC-seq]

Project description:The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [ATAC-seq]

| PRJNA481733 | ENA

The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [ChIP-seq]

Project description:The mSWI/SNF ATPase module mediates subcomplex identity and non-catalytic targeting in SCCOHT [ChIP-seq]

| PRJNA483038 | ENA

The BAF complex blocks Myogenesis in rhabdomyosarcoma

Project description:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer of skeletal muscle lineage. The aggressive alveolar subtype is commonly characterized by t(2;13) or t(1;13) translocations with the expression of PAX3- or PAX7-FOXO1 fusion transcription factors respectively and is known as fusion positive RMS (FP-RMS). FP-RMS tumors rely on the fusion gene to maintain their proliferative state while avoiding terminal differentiation program. Since disruptions of normal development are likely governed by epigenetic changes in these low-mutational-burden tumors, we investigated the contributions of chromatin regulatory complexes to RMS tumor maintenance. We demonstrate the essentiality of the mSWI/SNF ATPase BRG1 for FP-RMS proliferation and discover that RMS significantly overexpress SMARCA4 (encoding BRG1) compared to skeletal muscle. We define the mSWI/SNF subunit repertoire in FP-RMS and provide evidence for the assembly of multiple mSWI/SNF complexes including canonical BAF, PBAF and non-canonical (nc)BAF in FP-RMS. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which was further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with FP-RMS core regulatory transcription factors. We report that mSWI/SNF complexes act as sensors of chromatin state, which are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes. Finally, BRG1 targeting compounds reproduce the effects of genetic ablation. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for treating this lethal childhood tumor.

2021-04-01 | GSE162052 | GEO

Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation and genomic profiling

Project description:Mammalian SWI/SNF (mSWI/SNF or BAF) chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression and are comprised of three final-form assemblies, cBAF, PBAF, and ncBAF, which exhibit distinct modular organization, chromatin targeting, and roles in disease. However, the contributions of each subcomplex and their constituent subunits to gene expression remain incompletely defined. Here, we performed a large-scale CRISPR-Cas9 knockout screen targeting mSWI/SNF subunits individually and in selected combinations, followed by single-cell RNA-sequencing (Perturb-seq) and SHARE-Seq. We uncover complex- and module-specific contributions across cell regulatory pathways, define paralog subunit relationships, and identify shifted functions upon perturbations. Finally, we superimpose single-cell perturbation signatures over bulk primary human tumor gene expression profiles, defining unique subunit-specific signatures and identifying tumor features that mirror BAF loss-of-function. Taken together, these data highlight the utility of large-scale single-cell genomics to uncover gene expression and chromatin accessibility signatures in human disease states.

2023-04-05 | GSE200201 | GEO

Genome-wide chromatin profiles of PBRM1 [RNA-Seq]

Project description:PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler. The inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. Here we show that in VHL-deficient ccRCC tumors, PBRM1 loss results in an altered PBAF complex that retains the association between SMARCA4 and ARID2 but disengages BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proxy regions to distal enhancer regions. The ATPase function of SMARCA4 enhances the recruitment of nuclear factor RELA to aberrant sites and promotes NF-κB activity. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.

2023-02-13 | GSE152734 | GEO

Targeting SWI/SNF ATPases in H3.3K27M Diffuse Intrinsic Pontine Gliomas [ATAC-Seq]

Project description:Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling SWI/SNF complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2 and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells. AU-15330 lowered chromatin accessibility measured by ATAC-seq at non-promoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in levels of FOXO1, a key member of the forkhead family of transcription factors. Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M upregulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors.

2023-04-16 | GSE229453 | GEO

Targeting SWI/SNF ATPases in H3.3K27M Diffuse Intrinsic Pontine Gliomas [RNA-Seq]

2023-04-16 | GSE229452 | GEO

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