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TET2 coactivates gene expression through demethylation of enhancers.

著者 Wang L , Ozark PA , Smith ER , Zhao Z , Marshall SA , Rendleman EJ , Piunti A , Ryan C , Whelan AL , Helmin KA , Morgan MA , Zou L , Singer BD , Shilatifard A
Sci Adv.2018 Nov ; 4(11):eaau6986.
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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.
PMID: 30417100 [PubMed - in process]
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