title: A role for EZH2 in silencing of IFN-gamma inducible MHC2TA transcription in uveal melanoma.
abstract: We investigated the contribution of epigenetic mechanisms in MHC2TA transcriptional silencing in uveal melanoma. Although no correlation was observed between impaired CIITA transcript levels after IFN-gamma induction and DNA methylation of MHC2TA promoter IV (CIITA-PIV), an association was found with high levels of trimethylated histone H3-lysine 27 (3Me-K27-H3) in CIITA-PIV chromatin. The 3Me-K27-H3 modification correlated with a strong reduction in RNA polymerase II-recruitment to CIITA-PIV. Interestingly, we observed that none of these epigenetic modifications affected recruitment of activating transcription factors to this promoter. Subsequently, we demonstrated the presence of the histone methyltransferase EZH2 in CIITA-PIV chromatin, which is known to be a component of the Polycomb repressive complex 2 and able to triple methylate histone H3-lysine 27. RNA interference-mediated down-regulation of EZH2 expression resulted in an increase in CIITA transcript levels after IFN-gamma induction. Our data therefore reveal that EZH2 contributes to silencing of IFN-gamma-inducible transcription of MHC2TA in uveal melanoma cells.
authors.affiliation: Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tjadine M
authors.initials: TM
authors.lastname: Holling
authors.forename: Marloes W T
authors.initials: MW
authors.lastname: Bergevoet
authors.forename: Louis
authors.initials: L
authors.lastname: Wilson
authors.forename: Marja C J A
authors.initials: MC
authors.lastname: Van Eggermond
authors.forename: Erik
authors.initials: E
authors.lastname: Schooten
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van den Elsen
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000276:immunology; D034622:RNA Interference / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology; D014604:Uveal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2