G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression

Xi Zhang; Danni Peng; Yuanxin Xi; Chao Yuan; Cari A. Sagum; Brianna J. Klein; Kaori Tanaka; Hong Wen; Tatiana G. Kutateladze; Wei Li; Mark T. Bedford; Xiaobing Shi

doi:10.1038/ncomms10810

G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression

Xi Zhang, Danni Peng, Yuanxin Xi, Chao Yuan, Cari A. Sagum, Brianna J. Klein, Kaori Tanaka, Hong Wen, Tatiana G. Kutateladze, Wei Li, Mark T. Bedford, Xiaobing Shi

Epigenetics & Molecular Carcinogenesis

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

45 Scopus citations

Abstract

The euchromatin histone methyltransferase 2 (also known as G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a coactivator of the endogenous oestrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα at K235 both in vitro and in cells. Dimethylation of ERαK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression.

Original language	English (US)
Article number	10810
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10810
State	Published - Mar 10 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Protein Array and Analysis Core

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10.1038/ncomms10810

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@article{89d27202f5264adaaef3f4b36ff8579d,

title = "G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression",

abstract = "The euchromatin histone methyltransferase 2 (also known as G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a coactivator of the endogenous oestrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα at K235 both in vitro and in cells. Dimethylation of ERαK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression.",

author = "Xi Zhang and Danni Peng and Yuanxin Xi and Chao Yuan and Sagum, {Cari A.} and Klein, {Brianna J.} and Kaori Tanaka and Hong Wen and Kutateladze, {Tatiana G.} and Wei Li and Bedford, {Mark T.} and Xiaobing Shi",

note = "Funding Information: We thank M. Barton, J. Tyler, M. Lee, T. Jenuwein and Y. Tanaka for reagents. We thank Dr Briana Dennehey and Joseph Munch for comments and editing the manuscript. We thank the MD Anderson Sequencing and Microarray Facility and the Science Park Next-Generation Sequencing Facility (CPRIT RP120348) for Solexa sequencing and the Protein Array and Analysis Core (RP130432) for the protein domain array work. This work was supported by grants to X.S. (American Cancer Society RSG-13-290-01-TBE, CPRIT RP110471, RP140323, Welch G1719 and the Jeanne F. Shelby Scholarship Fund), W.L. (CPRIT RP110471, RP150292 and NIH HG007538), M.T.B. (CPRIT RP110471 and NIH DK062248) and T.G.K. (NIH GM101664). X.Z. is a MDACC Center for Cancer Epigenetics Postdoctoral Scholar. B.J.K. is an American Heart Association Postdoctoral Fellow. W.L. is a Duncan Scholar. X.S. is an R. Lee Clark Fellow.",

year = "2016",

month = mar,

day = "10",

doi = "10.1038/ncomms10810",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression

AU - Zhang, Xi

AU - Peng, Danni

AU - Xi, Yuanxin

AU - Yuan, Chao

AU - Sagum, Cari A.

AU - Klein, Brianna J.

AU - Tanaka, Kaori

AU - Wen, Hong

AU - Kutateladze, Tatiana G.

AU - Li, Wei

AU - Bedford, Mark T.

AU - Shi, Xiaobing

N1 - Funding Information: We thank M. Barton, J. Tyler, M. Lee, T. Jenuwein and Y. Tanaka for reagents. We thank Dr Briana Dennehey and Joseph Munch for comments and editing the manuscript. We thank the MD Anderson Sequencing and Microarray Facility and the Science Park Next-Generation Sequencing Facility (CPRIT RP120348) for Solexa sequencing and the Protein Array and Analysis Core (RP130432) for the protein domain array work. This work was supported by grants to X.S. (American Cancer Society RSG-13-290-01-TBE, CPRIT RP110471, RP140323, Welch G1719 and the Jeanne F. Shelby Scholarship Fund), W.L. (CPRIT RP110471, RP150292 and NIH HG007538), M.T.B. (CPRIT RP110471 and NIH DK062248) and T.G.K. (NIH GM101664). X.Z. is a MDACC Center for Cancer Epigenetics Postdoctoral Scholar. B.J.K. is an American Heart Association Postdoctoral Fellow. W.L. is a Duncan Scholar. X.S. is an R. Lee Clark Fellow.

PY - 2016/3/10

Y1 - 2016/3/10

N2 - The euchromatin histone methyltransferase 2 (also known as G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a coactivator of the endogenous oestrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα at K235 both in vitro and in cells. Dimethylation of ERαK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression.

AB - The euchromatin histone methyltransferase 2 (also known as G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a coactivator of the endogenous oestrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα at K235 both in vitro and in cells. Dimethylation of ERαK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression.

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U2 - 10.1038/ncomms10810

DO - 10.1038/ncomms10810

M3 - Article

C2 - 26960573

AN - SCOPUS:84960510627

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 10810

ER -

G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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