Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, MD 20814, USA.
Center for Biomedical Engineering, Brown University, Providence, RI 02912, USA.
J Cell Sci. 2021 Sep 1;134(17). doi: 10.1242/jcs.258578. Epub 2021 Sep 3.
Myxoid liposarcoma is caused by a chromosomal translocation resulting in a fusion protein comprised of the N terminus of FUS (fused in sarcoma) and the full-length transcription factor CHOP (CCAAT/enhancer-binding protein homologous protein, also known as DDIT3). FUS functions in RNA metabolism, and CHOP is a stress-induced transcription factor. The FUS-CHOP fusion protein causes unique gene expression and oncogenic transformation. Although it is clear that the FUS segment is required for oncogenic transformation, the mechanism of FUS-CHOP-induced transcriptional activation is unknown. Recently, some transcription factors and super enhancers have been proposed to undergo liquid-liquid phase separation and form membraneless compartments that recruit transcription machinery to gene promoters. Since phase separation of FUS depends on its N terminus, transcriptional activation by FUS-CHOP could result from the N terminus driving nuclear phase transitions. Here, we characterized FUS-CHOP in cells and in vitro, and observed novel phase-separating properties relative to unmodified CHOP. Our data indicate that FUS-CHOP forms phase-separated condensates that colocalize with BRD4, a marker of super enhancer condensates. We provide evidence that the FUS-CHOP phase transition is a novel oncogenic mechanism and potential therapeutic target for myxoid liposarcoma. This article has an associated First Person interview with the first author of the paper.
黏液样脂肪肉瘤是由染色体易位引起的，导致融合蛋白由 FUS（肉瘤中融合）的 N 端和全长转录因子 CHOP（CCAAT/增强子结合蛋白同源蛋白，也称为 DDIT3）组成。FUS 在 RNA 代谢中起作用，而 CHOP 是一种应激诱导的转录因子。FUS-CHOP 融合蛋白导致独特的基因表达和致癌转化。尽管很明显 FUS 片段是致癌转化所必需的，但 FUS-CHOP 诱导的转录激活机制尚不清楚。最近，一些转录因子和超级增强子被提出经历液-液相分离，并形成无膜隔间，将转录机制募集到基因启动子处。由于 FUS 的相分离依赖于其 N 端，因此 FUS-CHOP 的转录激活可能是由于 N 端驱动核相转变。在这里，我们在细胞和体外对 FUS-CHOP 进行了表征，并观察到相对于未修饰的 CHOP 的新的相分离特性。我们的数据表明，FUS-CHOP 形成相分离的凝聚物，与 BRD4 共定位，BRD4 是超级增强子凝聚物的标志物。我们提供的证据表明，FUS-CHOP 的相变是一种新的致癌机制，也是黏液样脂肪肉瘤的潜在治疗靶点。本文附有该论文第一作者的相关第一人称采访。
