Methylation of class II trans-activator promoter IV: a novel mechanism of MHC class II gene control.
Inhibition of class II trans-activator (CIITA) expression prevents embryonic trophoblast cells from up-regulating MHC class II genes in response to IFN-gamma. This is thought to be one mechanism of maternal tolerance to the fetal allograft. The CIITA gene is regulated by four distinct promoters; promoter III directs constitutive (B cell) expression, and promoter IV regulates IFN-gamma-inducible expression. Using in vivo genomic footprinting, promoter-reporter analysis, Southern blot analysis, and RT-PCR, we have examined the cause of CIITA silencing in a trophoblast-derived cell line. We report here that methylation of promoter IV DNA at CpG sites in Jar cells prevents promoter occupancy and IFN-gamma-inducible transcription. The inhibition of CpG methylation in Jar cells by treatment with 5-aza-2'-deoxycytidine restores IFN-gamma inducibility to CIITA. This is the first description of an epigenetic mechanism involved in regulation of CIITA and MHC class II gene expression.
Morris
A C
AC
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Spangler
W E
WE
Boss
J M
JM
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D002822:Choriocarcinoma; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005802:Genes, MHC Class II / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D000077209:Decitabine; D007371:Interferon-gamma; D015254:DNA Modification Methylases; D001374:Azacitidine