DNA甲基化
生物
DNMT1型
表观遗传学
癌症表观遗传学
DNA甲基转移酶
基因组印记
体育锻炼的表观遗传学
遗传学
DNMT3B型
癌症研究
甲基化
甲基转移酶
分子生物学
基因沉默
基因
基因表达
作者
Ina Rhee,Kurtis E. Bachman,Ben Ho Park,Kam Wing Jair,Ray Whay Chiu Yen,Kornel E. Schuebel,Hengmi Cui,Andrew P. Feinberg,Christoph Lengauer,Kenneth W. Kinzler,Stephen B. Baylin,Bert Vogelstein
出处
期刊:Nature
[Springer Nature]
日期:2002-04-01
卷期号:416 (6880): 552-556
被引量:1144
摘要
Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation.
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