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

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. Naïve synovial sarcoma cell lines (Aska,Yamato, HSSY2, YaFuSS, SYO1, Fuji) were grown in culture and RNA was harvested in biological duplicate for sequencing. Synovial sarcoma cell lines (Aska, HSSY2, SYO1) were lentivirally infected with either an shControl or a shSSX vector, selected for 48 hours with puromycin, then grown for either 1 day (3 days post-infection) or 5 days (7 days post-infection), at which point RNA was harvested from independent biological duplicate for sequencing. CRL7250 fibroblast cell line was lentivirally infected with either a V5-SS18 or V5-SS18-SSX expressing vector, selected for 48 hours with puromycin, then grown for 5 days, at which point RNA was harvested from independent biological duplicate for sequencing.