Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.
Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.
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DOI：
10.1016/j.molcel.2022.09.034
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发表时间：
2022-11-03
期刊：
影响因子：
16
通讯作者：
Wan, Liling
中科院分区：
文献类型：
--
作者：
Song, Lele;Yao, Xinyi;Li, Hangpeng;Peng, Bo;Boka, Alan P.;Liu, Yiman;Chen, Guochao;Liu, Zhenyang;Mathias, Kaeli M.;Xia, Lingbo;Li, Qinglan;Mir, Mustafa;Li, Yuanyuan;Li, Haitao;Wan, Liling
越来越多的证据表明，染色质上的转录缩合物的流行，但其形成机制和疾病中的功能意义仍不清楚。在人类癌症中，组蛋白乙酰化读取器ENL中的一系列突变产生具有增加的转录激活能力的功能获得性突变体。在这里，我们表明，这些突变，聚集在ENL的结构化乙酰基阅读YEATS域，触发异常冷凝在天然基因组靶点，通过多价同型和异型相互作用。从机制上讲，突变诱导的结构变化的YEATS域，ENL的两个无序区域的相反电荷，并纳入外源性延伸因子都需要ENL冷凝物的形成。广泛的诱变建立了冷凝物形成作为致癌基因激活的驱动因素。此外，ENL突变体的表达超过内源水平导致非功能性缩合物。我们的研究结果为癌症相关冷凝物提供了新的机制和功能见解，并支持冷凝物调节异常作为致癌机制。Song等人表明，ENL癌症突变通过多价同型和异型相互作用并以剂量依赖性方式触发基因组靶点处的异常冷凝物形成。干扰这些相互作用或过度表达ENL突变体破坏冷凝物形成和/或性质，导致致癌基因活化缺陷。
Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance in disease remain unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here we show that these mutations, clustered in ENL’s structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL’s two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism. Song et al show that ENL cancer mutations trigger aberrant condensate formation at genomic targets through multivalent homotypic and heterotypic interactions and in a dose-dependent manner. Perturbing these interactions or overexpressing ENL mutant disrupts condensate formation and/or properties, leading to defects in oncogenic gene activation.
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