TET2 coactivates gene expression through demethylation of enhancers.
Sci Adv
; 4(11): eaau6986, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-30417100
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 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas
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Elementos Facilitadores Genéticos
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Receptor alfa de Estrogênio
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Proteínas de Ligação a DNA
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Desmetilação
Tipo de estudo:
Etiology_studies
/
Incidence_studies
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Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Sci Adv
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos