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

doi:10.1038/s41586-019-1842-7

GSTDTAP > 地球科学

DOI	10.1038/s41586-019-1842-7
	Impaired cell fate through gain-of-function mutations in a chromatin reader
	Wan, Liling 1,16; Chong, Shasha 2,3; Xuan, Fan 4; Liang, Angela 1; Cui, Xiaodong 5,6; Gates, Leah 1; Carroll, Thomas S.7; Li, Yuanyuan 8; Feng, Lijuan 1; Chen, Guochao 8; Wang, Shu-Ping 9,10; Ortiz, Michael V.11; Daley, Sara K.12; Wang, Xiaolu 4; Xuan, Hongwen 4; Kentsis, Alex 11,13; Muir, Tom W.12; Roeder, Robert G.; Li, Haitao 8; Li, Wei 5,6,14; Tjian, Robert 2,3,15; Wen, Hong 4; Allis, C. David 1
	2020-05-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	577 期号:7788 页码:121-+
文章类型	Article
语种	英语
国家	USA; Peoples R China; Taiwan
英文关键词	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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000505617400037
WOS关键词	TRANSCRIPTION ; ELONGATION ; COMPLEX ; ENL ; TEFB ; AFF4
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281466
专题	地球科学资源环境科学气候变化
作者单位	1.Rockefeller Univ, Lab Chromatin Biol & Epigenet, 1230 York Ave, New York, NY 10021 USA; 2.Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA; 3.Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA; 4.Van Andel Inst, Ctr Epigenet, Grand Rapids, MI 49546 USA; 5.Baylor Coll Med, Div Biostat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA; 6.Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA; 7.Rockefeller Univ, Bioinformat Core, 1230 York Ave, New York, NY 10021 USA; 8.Tsinghua Univ, Sch Med, Dept Basic Med Sci, Beijing Adv Innovat Ctr Struct Biol,MOE Key Lab P, Beijing, Peoples R China; 9.Rockefeller Univ, Lab Biochem & Mol Biol, 1230 York Ave, New York, NY 10021 USA; 10.Acad Sinica, Inst Biomed Sci, Taipei, Taiwan; 11.Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA; 12.Princeton Univ, Dept Chem, Princeton, NJ 08544 USA; 13.Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, Sloan Kettering Inst, 1275 York Ave, New York, NY 10021 USA; 14.Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92717 USA; 15.Univ Calif Berkeley, CIRM Ctr Excellence, Berkeley, CA 94720 USA; 16.Univ Penn, Dept Canc Biol, Perelman Sch Med, Philadelphia, PA 19104 USA
推荐引用方式 GB/T 7714	Wan, Liling,Chong, Shasha,Xuan, Fan,et al. Impaired cell fate through gain-of-function mutations in a chromatin reader[J]. NATURE,2020,577(7788):121-+.
APA	Wan, Liling.,Chong, Shasha.,Xuan, Fan.,Liang, Angela.,Cui, Xiaodong.,...&Allis, C. David.(2020).Impaired cell fate through gain-of-function mutations in a chromatin reader.NATURE,577(7788),121-+.
MLA	Wan, Liling,et al."Impaired cell fate through gain-of-function mutations in a chromatin reader".NATURE 577.7788(2020):121-+.