TET2 coactivates gene expression through demethylation of enhancers

Lu Wang, Patrick A. Ozark, Edwin 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 Singer, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)

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

Fingerprint

DNA Methylation
Estrogen Receptors
Estrogens
Clustered Regularly Interspaced Short Palindromic Repeats
5-Methylcytosine
Gene Expression
Dioxygenases
DNA
Gene Expression Regulation
Epigenomics
Antibody Formation
Enzymes
Neoplasms
5-hydroxymethylcytosine

ASJC Scopus subject areas

  • General

Cite this

Wang, Lu ; Ozark, Patrick A. ; Smith, Edwin ; 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 ; Shilatifard, Ali. / TET2 coactivates gene expression through demethylation of enhancers. In: Science Advances. 2018 ; Vol. 4, No. 11.
@article{c70fb8860f894ca4ace348177890fe3e,
title = "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 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.",
author = "Lu Wang and Ozark, {Patrick A.} and Edwin Smith and Zibo Zhao and Marshall, {Stacy A.} and Rendleman, {Emily J.} and Andrea Piunti and Caila Ryan and Whelan, {Anna L.} and Helmin, {Kathryn A.} and Morgan, {Marc Alard} and Lihua Zou and Benjamin Singer and Ali Shilatifard",
year = "2018",
month = "11",
day = "7",
doi = "10.1126/sciadv.aau6986",
language = "English (US)",
volume = "4",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "11",

}

Wang, L, Ozark, PA, Smith, E, Zhao, Z, Marshall, SA, Rendleman, EJ, Piunti, A, Ryan, C, Whelan, AL, Helmin, KA, Morgan, MA, Zou, L, Singer, B & Shilatifard, A 2018, 'TET2 coactivates gene expression through demethylation of enhancers', Science Advances, vol. 4, no. 11, eaau6986. https://doi.org/10.1126/sciadv.aau6986

TET2 coactivates gene expression through demethylation of enhancers. / Wang, Lu; Ozark, Patrick A.; Smith, Edwin; 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; Shilatifard, Ali.

In: Science Advances, Vol. 4, No. 11, eaau6986, 07.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TET2 coactivates gene expression through demethylation of enhancers

AU - Wang, Lu

AU - Ozark, Patrick A.

AU - Smith, Edwin

AU - Zhao, Zibo

AU - Marshall, Stacy A.

AU - Rendleman, Emily J.

AU - Piunti, Andrea

AU - Ryan, Caila

AU - Whelan, Anna L.

AU - Helmin, Kathryn A.

AU - Morgan, Marc Alard

AU - Zou, Lihua

AU - Singer, Benjamin

AU - Shilatifard, Ali

PY - 2018/11/7

Y1 - 2018/11/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85056347444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056347444&partnerID=8YFLogxK

U2 - 10.1126/sciadv.aau6986

DO - 10.1126/sciadv.aau6986

M3 - Article

C2 - 30417100

AN - SCOPUS:85056347444

VL - 4

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 11

M1 - eaau6986

ER -