Abstract
SS18–SSX targets BAF complexes away from enhancers to broad domains where they activate bivalent genes.
Major finding: SS18–SSX targets BAF complexes away from enhancers to broad domains where they activate bivalent genes.
Mechanism: SS18–SSX-containing BAF complexes oppose PRC2-mediated repression at broad polycomb domains.
Impact: Synovial sarcoma is transcriptionally distinct from other malignancies driven by aberrant BAF complexes.
Synovial sarcoma is characterized by a chromosomal translocation that generates the SS18–SSX fusion oncoprotein. SS18 is a subunit of the BAF (SWI/SNF) chromatin remodeling complex, and SS18–SSX dominantly incorporates into BAF complexes, replacing wild-type SS18 and triggering the eviction of the BAF47 tumor suppressor subunit. In order to elucidate the mechanism by which BAF complexes containing SS18–SSX promote tumorigenesis, McBride, Pulice, and colleagues performed chromatin immunoprecipitation sequencing to determine the genome-wide occupancy of wild-type SS18, SS18–SSX, and the core BAF complex subunits BAF155 and BRG1 in a synovial sarcoma cell line with and without SS18–SSX depletion. SS18–SSX promoted genome-wide targeting of BAF complexes to broad domains distinct from wild-type BAF complexes. RNA sequencing demonstrated that SS18–SSX BAF complexes directly activated a consistent set of oncogenic target genes across synovial sarcoma cell lines, and analysis of primary synovial sarcomas revealed distinct genomes and transcriptomes distinct from those of other tumors driven by BAF complex perturbations. Synovial sarcomas exhibited a low mutational burden and could be split into subgroups based on expression of the myogenic genes PAX3 and PAX7 or the largely mutually exclusive expression of MYC. There was a high degree of overlap between sites occupied by BAF complexes and PRC2 complexes. Mechanistically, SS18–SSX retargeted BAF complexes away from enhancers to broad polycomb domains, thereby opposing PRC2-mediated gene repression and recruiting RNA Pol II to activate transcription of bivalent genes. Suppression of SS18–SSX induced a proliferative arrest in synovial sarcoma cells that could not be rescued by BAF47-mediated enhancer activation, indicating that BAF47 eviction is not sufficient to explain the oncogenic function of SS18–SSX. Altogether, these findings define a mechanism by which SS18–SSX retargets BAF complexes from enhancers to activate broad polycomb domains to drive synovial sarcoma.
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