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.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Danni
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Cari A
authors.initials: CA
authors.lastname: Sagum
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Brianna J
authors.initials: BJ
authors.lastname: Klein
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
authors.affiliation: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Wei
authors.identifier: http://orcid.org/0000-0001-9931-5990
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Xiaobing
authors.identifier: http://orcid.org/0000-0001-5242-8189
authors.initials: X
authors.lastname: Shi
mesh_terms: D000107:Acetylation; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D051958:Nuclear Receptor Coactivator 2; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006649:Histocompatibility Antigens; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; C440091:PHF20 protein, human; D014157:Transcription Factors; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human