PDF(Pubmed)
Abstract：
Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing\'s sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing\'s sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing\'s sarcoma.
摘要：
液-液相分离（LLPS）促进细胞内无膜细胞器的形成，影响各种生物过程和疾病状态。富含AT的含相互作用域的蛋白1A（ARID1A）是一种经常与癌症突变相关的染色质重塑因子。然而，其功能机制在很大程度上仍然未知。这里,我们发现ARID1A有一个类病毒结构域(PrLD)，这有助于通过PrLD介导的LLPS形成液体冷凝物。在尤文氏肉瘤患者标本中，ARID1ALLPS形成的核缩合物显着升高。ARID1ALLPS的破坏导致尤文氏肉瘤细胞的增殖和侵袭能力降低。通过全基因组染色质结构和转录分析，我们发现ARID1A缩合物定位于EWS/FLI1靶增强剂,并通过在致癌靶基因上形成功能性染色质重塑中心,诱导长程染色质结构改变.总的来说，我们的研究结果表明，ARID1A通过PrLD介导的LLPS促进致癌潜力，为治疗尤因肉瘤提供了一种潜在的治疗方法。
