TET2 coactivates gene expression through demethylation of enhancers

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*

*Corresponding author for this work

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15 Scopus citations

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.

Original languageEnglish (US)
Article numbereaau6986
JournalScience Advances
Volume4
Issue number11
DOIs
StatePublished - Nov 7 2018

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ASJC Scopus subject areas

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Cite this

Wang, L., Ozark, P. A., Smith, E. R., Zhao, Z., Marshall, S. A., Rendleman, E. J., Piunti, A., Ryan, C., Whelan, A. L., Helmin, K. A., Morgan, M. A., Zou, L., Singer, B. D., & Shilatifard, A. (2018). TET2 coactivates gene expression through demethylation of enhancers. Science Advances, 4(11), [eaau6986]. https://doi.org/10.1126/sciadv.aau6986