染色質閱讀器功能突變導致細胞命運受損
作者：
小柯機器人發布時間：2019/12/19 15:00:11
美國洛克菲勒大學C. David Allis、萬裡玲和美國範安德爾研究所表觀遺傳學中心Hong Wen等研究團隊合作，發現染色質閱讀器中的功能獲得突變導致細胞命運受損。2019年12月18日，《自然》在線發表了這項成果。
他們先前通過其YEATS結構域將ENL蛋白鑑定為組蛋白乙醯化的閱讀器，並將其與急性白血病中癌症驅動基因的表達聯繫起來。在Wilms tumour（最常見的小兒腎癌）的ENL YEATS結構域中發現了反覆出現的熱點突變。他們表示使用人類和小鼠細胞，這些突變通過賦予染色質募集和轉錄控制功能來損傷細胞命運的調控。ENL突變體誘導了有利於癌前細胞命運的基因表達變化，並且在使用鼠細胞進行的腎生成實驗中，導致未分化的結構類似於在人類Wilms腫瘤中觀察到的結構。從機制上講，儘管與野生型蛋白結合的基因組基因座在很大程度上相似，但ENL突變體在靶標亞群上的佔有率增加，導致轉錄延伸機制的募集和活性顯著增加，從而增強了從靶基因座的主動轉錄。此外，異位表達的ENL突變體表現出更大的自我關聯，並形成離散的動態核點，這是由局部高濃度調節因子組成的生物分子集線器的特徵。這種突變驅動的ENL自我締合在功能上與染色質佔有率和基因激活增強有關。總的來說，他們的發現表明，染色質閱讀器結構域中的熱點突變驅動自增強的募集，破壞了發育過程中正常的細胞命運控制，並導致了致癌發生。
據介紹，組蛋白的修飾在正常發育和人類疾病中具有重要作用。「閱讀器」蛋白識別修飾的組蛋白是介導組蛋白修飾功能的關鍵機制，但這些閱讀器的失調可能如何導致疾病仍知之甚少。
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