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

doi:10.1126/sciadv.aau6986

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

Research output: Contribution to journal › Article › peer-review

69 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 language	English (US)
Article number	eaau6986
Journal	Science Advances
Volume	4
Issue number	11
DOIs	https://doi.org/10.1126/sciadv.aau6986
State	Published - Nov 7 2018

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@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 Smith, {Edwin R.} 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 Singer, {Benjamin D.} and Ali Shilatifard",

note = "Funding Information: This work was supported by the Training Program in Signal Transduction and Cancer (grant T32 CA070085 to L.W.); NIH/NCI training grant T32CA070085, Alex's Lemonade Stand Foundation, and Northwestern Mutual (to Z.Z.); NIH grant R50CA211428 (to E.R.S.); and NIH grant K08HL128867 and the Francis Family Foundation's Parker B. Francis Research Opportunity Award (to B.D.S.). Studies in the Shilatifard laboratory related to COMPASS are supported by the NCI's Outstanding Investigator Award R35CA197569 to A.S. Publisher Copyright: Copyright {\textcopyright} 2018 The Authors, some rights reserved.",

year = "2018",

month = nov,

day = "7",

doi = "10.1126/sciadv.aau6986",

language = "English (US)",

volume = "4",

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T1 - TET2 coactivates gene expression through demethylation of enhancers

AU - Wang, Lu

AU - Ozark, Patrick A.

AU - Smith, Edwin R.

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 D.

AU - Shilatifard, Ali

N1 - Funding Information: This work was supported by the Training Program in Signal Transduction and Cancer (grant T32 CA070085 to L.W.); NIH/NCI training grant T32CA070085, Alex's Lemonade Stand Foundation, and Northwestern Mutual (to Z.Z.); NIH grant R50CA211428 (to E.R.S.); and NIH grant K08HL128867 and the Francis Family Foundation's Parker B. Francis Research Opportunity Award (to B.D.S.). Studies in the Shilatifard laboratory related to COMPASS are supported by the NCI's Outstanding Investigator Award R35CA197569 to A.S. Publisher Copyright: Copyright © 2018 The Authors, some rights reserved.

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.

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TET2 coactivates gene expression through demethylation of enhancers

Abstract

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