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TET2 coactivates gene expression through demethylation of enhancers

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 ERalpha. 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 ERalpha, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120756 | GEO | 2018/10/04

REPOSITORIES: GEO

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