The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.

SS18-SSX 融合通过将 mSWI/SNF (BAF) 复合体成员 SS18 与 Polycomb 抑制复合体 1 (PRC1) 靶基因桥接，驱动滑膜肉瘤中的致癌转化。在这里，我们表明 SS18-SSX 占据 H2AK119ub1 丰富区域的能力是其 SSX C 末端的固有特性，可以通过与 SS18 之外的转录调节因子融合来利用。因此，SS18-SSX 的招募方式独立于 BAF 的核心成分和催化活性。替代的 SSX 融合体也被招募到富含 H2AK119ub1 的染色质，并通过与转录激活剂结合来重现 SS18-SSX 的表达特征。变体 Polycomb 抑制复合体 1.1 (PRC1.1) 充当 H2AK119ub1 的主要沉积者，因此是 SS18-SSX 占用所必需的。重要的是，SSX C 端不仅依赖于 H2AK119ub1 进行本地化，而且还通过促进 PRC1.1 复合体稳定性来进一步增强 H2AK119ub1。因此，高 H2AK119ub1 水平是小鼠和人类滑膜肉瘤的一个特征。这些结果揭示了 SSX-C 通过提供染色质特异性并通过增强 PRC1.1 稳定性和 H2AK119ub1 沉积进一步实现肿瘤融合结合，在介导滑膜肉瘤基因失调中发挥关键作用。