Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Chemical Biology, Harvard University, Cambridge, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cancer Cell. 2018 Jun 11;33(6):1128-1141.e7. doi: 10.1016/j.ccell.2018.05.002. Epub 2018 May 31.
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.
滑膜肉瘤 (SS) 由标志性的 SS18-SSX 融合致癌蛋白定义，该蛋白以两种方式使 BAF 复合物异常：SSX 获得 SS18 亚基，同时丧失 BAF47 亚基组装。在这里，我们证明 SS18-SSX 全局劫持染色质上的 BAF 复合物，激活我们使用原发性肿瘤和细胞系定义的 SS 转录特征。具体而言，SS18-SSX 将 BAF 复合物从增强子重新靶向到广泛的多梳域，以对抗 PRC2 介导的抑制并激活双价基因。抑制 SS18-SSX 后，BAF47 的重新组装恢复了增强子的激活，但对于增殖抑制不是必需的。这些结果确立了 SS18-SSX 在染色质上的全局劫持机制，并定义了两种同时发生的 BAF 复合物扰动的独特贡献。
