DNA去甲基化
增强子
表观遗传学
去甲基化
基因表达
基因
生物
基因表达调控
遗传学
5-羟甲基胞嘧啶
雌激素受体
DNA
分子生物学
DNA甲基化
癌症
乳腺癌
作者
Lu Wang,Patrick A. Ozark,Edwin R. Smith,Zibo Zhao,Stacy A. Marshall,Emily J. Rendleman,Andrea Piunti,Caila Ryan,Anna L. Whelan,Kathryn A. Helmin,Marc A. Morgan,Lihua Zou,Benjamin D. Singer,Ali Shilatifard
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2018-11-02
卷期号:4 (11)
被引量:86
标识
DOI:10.1126/sciadv.aau6986
摘要
The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of the modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss of TET2 is associated with changes in DNA methylation patterns. Here, using newly developed TET2-specific antibodies and the estrogen response as a model system for studying the regulation of gene expression, we demonstrate that endogenous TET2 occupies active enhancers and facilitates the proper recruitment of estrogen receptor α (ERα). Knockout of TET2 by CRISPR-CAS9 leads to a global increase of DNA methylation at enhancers, resulting in attenuation of the estrogen response. We further identified a positive feedback loop between TET2 and ERα, which further requires MLL3 COMPASS at these enhancers. Together, this study reveals an epigenetic axis coordinating a transcriptional program through enhancer activation via DNA demethylation.
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