Impaired cell fate through gain-of-function mutations in a chromatin reader
Impaired cell fate through gain-of-function mutations in a chromatin reader
复制标题
DOI：
10.1038/s41586-019-1842-7
复制
发表时间：
2020-01-02
期刊：
影响因子：
64.8
通讯作者：
Allis, C. David
中科院分区：
文献类型：
--
作者：
Wan, Liling;Chong, Shasha;Allis, C. David
组蛋白的修饰在正常发育和人类疾病中具有重要作用。 “阅读器”蛋白对修饰组蛋白的识别是介导组蛋白修饰功能的关键机制，但这些阅读器的失调如何导致疾病仍知之甚少。我们之前发现 ENL 蛋白通过其 YEATS 结构域作为组蛋白乙酰化的读取器，将其与急性白血病中癌症驱动基因的表达联系起来。在最常见的儿童肾癌类型 Wilms tumour2,3 的 ENL YEATS 结构域中发现了复发性热点突变。在这里，我们使用人类和小鼠细胞证明，这些突变通过赋予染色质招募和转录控制功能获得性而损害细胞命运调节。 ENL突变体诱导有利于癌前细胞命运的基因表达变化，并且在使用鼠细胞的肾发生测定中，导致类似于人类肾母细胞瘤中观察到的未分化结构。从机制上讲，虽然与野生型蛋白结合在很大程度上相似的基因组位点，但 ENL 突变体表现出对靶标子集的占有率增加，导致转录延伸机制的招募和活性显着增加，从而强制从靶位点进行主动转录。此外，异位表达的 ENL 突变体表现出更大的自关联性，并形成离散且动态的核点，这是由局部高浓度调节因子组成的生物分子中心的特征。这种突变驱动的 ENL 自关联在功能上与增强的染色质占据和基因激活有关。总的来说，我们的研究结果表明，染色质阅读器结构域中的热点突变会驱动自我强化的募集，破坏发育过程中正常的细胞命运控制，并导致致癌结果。
Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatinreader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.