小柯机器人

染色质阅读器功能突变导致细胞命运受损
2019-12-19 15:00

美国洛克菲勒大学C. David Allis、万里玲和美国范安德尔研究所表观遗传学中心Hong Wen等研究团队合作,发现染色质阅读器中的功能获得突变导致细胞命运受损。2019年12月18日,《自然》在线发表了这项成果。

他们先前通过其YEATS结构域将ENL蛋白鉴定为组蛋白乙酰化的阅读器,并将其与急性白血病中癌症驱动基因的表达联系起来。在Wilms tumour(最常见的小儿肾癌)的ENL YEATS结构域中发现了反复出现的热点突变。他们表示使用人类和小鼠细胞,这些突变通过赋予染色质募集和转录控制功能来损伤细胞命运的调控。ENL突变体诱导了有利于癌前细胞命运的基因表达变化,并且在使用鼠细胞进行的肾生成实验中,导致未分化的结构类似于在人类Wilms肿瘤中观察到的结构。从机制上讲,尽管与野生型蛋白结合的基因组基因座在很大程度上相似,但ENL突变体在靶标亚群上的占有率增加,导致转录延伸机制的募集和活性显着增加,从而增强了从靶基因座的主动转录。此外,异位表达的ENL突变体表现出更大的自我关联,并形成离散的动态核点,这是由局部高浓度调节因子组成的生物分子集线器的特征。这种突变驱动的ENL自我缔合在功能上与染色质占有率和基因激活增强有关。总的来说,他们的发现表明,染色质阅读器结构域中的热点突变驱动自增强的募集,破坏了发育过程中正常的细胞命运控制,并导致了致癌发生。

据介绍,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”蛋白识别修饰的组蛋白是介导组蛋白修饰功能的关键机制,但这些阅读器的失调可能如何导致疾病仍知之甚少。

附:英文原文

Title: Impaired cell fate through gain-of-function mutations in a chromatin reader

Author: Liling Wan, Shasha Chong, Fan Xuan, Angela Liang, Xiaodong Cui, Leah Gates, Thomas S. Carroll, Yuanyuan Li, Lijuan Feng, Guochao Chen, Shu-Ping Wang, Michael V. Ortiz, Sara K. Daley, Xiaolu Wang, Hongwen Xuan, Alex Kentsis, Tom W. Muir, Robert G. Roeder, Haitao Li, Wei Li, Robert Tjian, Hong Wen, C. David Allis

Issue&Volume: 2019-12-18

Abstract: 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 chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome. The histone-acetylation-reader protein ENL is mutated in a paediatric kidney cancer in such a way that it clusters at target genes, increasing the recruitment of the transcriptional machinery, enhancing transcription and deregulating cell fate during development.

DOI: 10.1038/s41586-019-1842-7

Source:https://www.nature.com/articles/s41586-019-1842-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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