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The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial SarcomaMcBride, Matthew J.; Pulice, John L.; Beird, Hannah C.; Ingram, Davis R.; D’Avino, Andrew R.; Shern, Jack F.; Charville, Gregory W.; Hornick, Jason L.; Nakayama, Robert T.; Garcia-Rivera, Enrique M.; Araujo, Dejka M.; Wang, Wei-Lien; Tsai, Jen-Wei; Yeagley, Michelle; Wagner, Andrew J.; Futreal, P. Andrew; Khan, Javed; Lazar, Alexander J.; Kadoch, Cigall
Cancer cell, 06/2018, Volume: 33, Issue: 6Journal Article
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 an SS transcriptional signature that 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. Display omitted •SS18-SSX assembly results in concurrent gains and losses in genome-wide BAF complex targeting•Synovial sarcoma is transcriptionally distinct from other BAF complex-driven malignancies•SS18-SSX targets BAF complexes to broad polycomb domains to activate bivalent genes•BAF47 reassembly activates enhancers but is dispensable for proliferative arrest Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.
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