TET2 coactivates gene expression through demethylation of enhancers

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...

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Bibliographic Details
Published in:Science advances 2018-11, Vol.4 (11), p.eaau6986-eaau6986
Main Authors: Wang, Lu, Ozark, Patrick A, Smith, Edwin R, Zhao, Zibo, Marshall, Stacy A, Rendleman, Emily J, Piunti, Andrea, Ryan, Caila, Whelan, Anna L, Helmin, Kathryn A, Morgan, Marc Alard, Zou, Lihua, Singer, Benjamin D, Shilatifard, Ali
Format: Article
Language:English
Subjects:
Biochemistry
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Differentiation
Cohort Studies
CRISPR-Cas Systems
Demethylation
Dioxygenases
DNA Methylation
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enhancer Elements, Genetic
Epigenesis, Genetic
Estrogen Receptor alpha - antagonists & inhibitors
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Female
Gene Expression Regulation, Neoplastic
Genetics
Humans
Molecular Biology
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
SciAdv r-articles
Survival Rate
Tumor Cells, Cultured
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aau6986