A role for EZH2 in silencing of IFN-gamma inducible MHC2TA transcription in uveal melanoma.
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.
Holling
Tjadine M
TM
Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Bergevoet
Marloes W T
MW
Wilson
Louis
L
Van Eggermond
Marja C J A
MC
Schooten
Erik
E
Steenbergen
Renske D M
RD
Snijders
Peter J F
PJ
Jager
Martine J
MJ
Van den Elsen
Peter J
PJ
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
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