Interactions between chromatin-associated proteins and the histone landscape play major roles in dictating genome topology and gene expression. Cancer-specific fusion oncoproteins, which display unique chromatin localization patterns, often lack classical DNA-binding domains, presenting challenges in identifying mechanisms governing their site-specific chromatin targeting and function. Here we identify a minimal region of the human SS18-SSX fusion oncoprotein (the hallmark driver of synovial sarcoma) that mediates a direct interaction between the mSWI/SNF complex and the nucleosome acidic patch. This binding results in altered mSWI/SNF composition and nucleosome engagement, driving cancer-specific mSWI/SNF complex targeting and gene expression. Furthermore, the C-terminal region of SSX confers preferential affinity to repressed, H2AK119Ub-marked nucleosomes, underlying the selective targeting to polycomb-marked genomic regions and synovial sarcoma–specific dependency on PRC1 function. Together, our results describe a functional interplay between a key nucleosome binding hub and a histone modification that underlies the disease-specific recruitment of a major chromatin remodeling complex.

染色质相关蛋白和组蛋白景观之间的相互作用在决定基因组拓扑结构和基因表达方面发挥着重要作用。癌症特异性融合癌蛋白表现出独特的染色质定位模式，通常缺乏经典的 DNA 结合结构域，这在识别控制其位点特异性染色质靶向和功能的机制方面提出了挑战。在这里，我们确定了人类 SS18-SSX 融合癌蛋白（滑膜肉瘤的标志性驱动因素）的最小区域，该区域介导 mSWI/SNF 复合物和核小体酸性斑块之间的直接相互作用。这种结合导致 mSWI/SNF 组成和核小体参与改变，从而驱动癌症特异性 mSWI/SNF 复合物靶向和基因表达。此外，SSX 的 C 末端区域赋予受抑制的优先亲和力，H2AK119Ub 标记的核小体，是选择性靶向多梳标记基因组区域和滑膜肉瘤对 PRC1 功能的特异性依赖的基础。总之，我们的结果描述了关键核小体结合中心和组蛋白修饰之间的功能相互作用，该修饰是主要染色质重塑复合物疾病特异性募集的基础。