TET2 coactivates gene expression through demethylation of enhancers

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Abstract

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 ER?, 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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Wang, L., Ozark, P. A., Smith, E. R., Zhao, Z., Marshall, S. A., Rendleman, E. J., … Shilatifard, A. (2018). TET2 coactivates gene expression through demethylation of enhancers. Science Advances, 4(11). https://doi.org/10.1126/sciadv.aau6986

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