The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma.

The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma.
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DOI:
10.1016/j.ccell.2018.05.002
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发表时间:
2018-06-11
期刊:
影响因子:
50.3
通讯作者:
Kadoch C
Kadoch C
中科院分区:
医学1区
文献类型:
--
作者:
McBride MJ;Pulice JL;Beird HC;Ingram DR;D'Avino AR;Shern JF;Charville GW;Hornick JL;Nakayama RT;Garcia-Rivera EM;Araujo DM;Wang WL;Tsai JW;Yeagley M;Wagner AJ;Futreal PA;Khan J;Lazar AJ;Kadoch C

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滑膜肉瘤 (SS) 是由标志性 SS18-SSX 融合癌蛋白定义的,该蛋白以两种方式导致 BAF 复合物异常:SS18 亚基获得 SSX 并同时损失 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,以激活我们使用原发性肿瘤和细胞系定义的 SS 转录特征。具体来说,SS18-SSX 将 BAF 复合物从增强子重新定位到广泛的多梳结构域,以对抗 PRC2 介导的抑制并激活二价基因。抑制 SS18-SSX 后,BAF47 的重新组装可恢复增强子激活,但不是增殖抑制所必需的。这些结果建立了染色质上 SS18-SSX 的全局劫持机制,并定义了两个并发 BAF 复合物扰动的独特贡献。将滑膜肉瘤 SS18-SSX 融合体纳入 BAF 复合物会导致 BAF47 的同时驱逐。麦克布莱德等人。显示 SS18-SSX 将 BAF 复合物从增强子重新定位到多梳结构域,以对抗 PRC2 介导的抑制。抑制 SS18-SSX 后 BAF47 的重新掺入可恢复增强子激活,但不是增殖抑制所必需的。
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.
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