Abstract
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. 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.
Original language | English (US) |
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Pages (from-to) | 1128-1141.e7 |
Journal | Cancer cell |
Volume | 33 |
Issue number | 6 |
DOIs | |
State | Published - Jun 11 2018 |
Keywords
- ATP-dependent chromatin remodeling
- SWI/SNF (BAF) complexes
- bivalency
- chromatin
- enhancers
- fusion oncoprotein
- pediatric cancer
- polycomb
- synovial sarcoma
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research