Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.

中文翻译：

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F病毒样结构域对BAF复合物的癌症特异性重定目标。

转录调节因子的改变可以协调癌症中的致癌基因表达程序。在这里，我们显示BRG1 / BRM相关因子（BAF）染色质重塑复合物在超过20％的人类肿瘤中发生了突变，它与EWSR1相互作用，EWSR1是具有病毒样结构域（PrLD）的蛋白质家族的成员在与转录因子的致癌融合中是常见的合作伙伴。在尤因肉瘤中，我们发现BAF复合物被EWS-FLI1融合蛋白募集到肿瘤特异性增强子，并有助于靶基因激活。与野生型FLI1相比，此过程是EWS-FLI1的新形态，并且依赖于EWSR1 ion病毒样结构域的相变所必需的酪氨酸残基。此外，EWSR1的短片段与FLI1的融合足以概括BAF复合物的靶向和EWS-FLI1的活性。因此，我们的研究表明病毒样结构域的物理性质可以将关键的染色质调节复合物重新定位，以建立和维持致癌基因表达程序。