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SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters [ChIP-Seq]

ABSTRACT: BAF complex perturbations contribute to over 20% of human cancer, yet the mechanisms by which these alterations drive oncogenesis remain poorly understood. The driving role for BAF complex mutations in cancer was first documented in malignant rhabdoid tumor (MRT), an aggressive pediatric cancer in which loss of SMARCB1 (also known as BAF47, INI1, hSNF5), a core BAF complex subunit, is the hallmark genetic alteration. We find that loss of BAF47 destabilizes the biochemical affinity of BAF complexes on chromatin without significantly impairing complex integrity or subunit composition. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in global increases in BAF complex occupancy, which mediates a major gain in enhancer activation. In addition, we find BAF47 targets BAF complexes to bivalent promoters, resolving bivalency to activation through opposition of polycomb-mediated repression. These findings demonstrate collaborative gene activation by the BAF complex through distinct mechanisms, highlighting specific BAF complex functions that are coopted or abated to drive human cancers and developmental disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90631 | GEO | 2017/09/25

REPOSITORIES: GEO

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SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters [Hi-C]

Project description:BAF complex perturbations contribute to over 20% of human cancer, yet the mechanisms by which these alterations drive oncogenesis remain poorly understood. The driving role for BAF complex mutations in cancer was first documented in malignant rhabdoid tumor (MRT), an aggressive pediatric cancer in which loss of SMARCB1 (also known as BAF47, INI1, hSNF5), a core BAF complex subunit, is the hallmark genetic alteration. We find that loss of BAF47 destabilizes the biochemical affinity of BAF complexes on chromatin without significantly impairing complex integrity or subunit composition. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in global increases in BAF complex occupancy, which mediates a major gain in enhancer activation. In addition, we find BAF47 targets BAF complexes to bivalent promoters, resolving bivalency to activation through opposition of polycomb-mediated repression. These findings demonstrate collaborative gene activation by the BAF complex through distinct mechanisms, highlighting specific BAF complex functions that are coopted or abated to drive human cancers and developmental disorders.

2017-09-25 | GSE90632 | GEO

SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters [RNA-Seq]

2017-09-25 | GSE90633 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [RNA-Seq Cell]

Project description:Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate a SS transcriptional signature we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

2018-05-31 | GSE108026 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [RNA-Seq Tumor]

2018-05-31 | GSE108027 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [ATAC-seq]

2018-05-31 | GSE114487 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [ChIP-Seq]

2018-05-31 | GSE108025 | GEO

ena-DATASET-MDACC-29-05-2018-15:47:46:325-962 - samples

Project description:Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

| EGAD00001004135 | EGA

SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

| EGAS00001002920 | EGA

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [primary tissue_RNA-seq]

Project description:SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.

2016-11-21 | GSE71503 | GEO

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [cell line_RNA-seq]

2016-11-21 | GSE71505 | GEO

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