TET2 coactivates gene expression through demethylation of enhancers

• DOI: 10.1126/sciadv.aau6986
• Publication Date: 2018-11-07T19:05:25Z
• Authors: 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 Alard Morgan; Lihua Zou; Benjamin D. Singer; Ali Shilatifard
• Keywords: DNA demethylation; 5-Hydroxymethylcytosine; Demethylation

The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss associated with changes methylation patterns. Here, using newly developed TET2-specific antibodies estrogen response as a model system for studying regulation gene expression, we demonstrate that endogenous occupies active enhancers facilitates proper recruitment receptor α (ERα). Knockout by CRISPR-CAS9 leads global increase at enhancers, resulting attenuation response. We further identified positive feedback loop between ERα, which requires MLL3 COMPASS these enhancers. Together, this study reveals an epigenetic axis coordinating transcriptional program through enhancer activation via demethylation.