title: Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression.
abstract: Class II major histocompatibility (MHC-II) genes are prototype targets of IFN-gamma. IFN-gamma activates the expression of the non-DNA-binding master regulator of MHC-II, class II transactivator (CIITA), which is crucial for enhanceosome formation and gene activation. This report shows the importance of the histone methyltransferase, coactivator-associated arginine methyltransferase (CARM1/PRMT4), during IFN-gamma-induced MHC-II gene activation. It also demonstrates the coordinated regulation of CIITA, CARM1, and the acetyltransferase cyclic-AMP response element binding (CREB)-binding protein (CBP) during this process. CARM1 synergizes with CIITA in activating MHC-II transcription and synergy is abrogated when an arginine methyltransferase-defective CARM1 mutant is used. Protein-arginine methyltransferase 1 has much less effect on MHC-II transcription. Specific RNA interference reduced CARM1 expression as well as MHC-II expression. The recruitment of CARM1 to the promoter requires endogenous CIITA and results in methylation of histone H3-R17; hence, CIITA is an upstream regulator of histone methylation. Previous work has shown that CARM1 can methylate CBP at three arginine residues. Using wild-type CBP and a mutant of CBP lacking the CARM1-targeted arginine residues (R3A), we show that arginine methylation of CBP is required for IFN-gamma induction of MHC-II. A kinetic analysis shows that CIITA, CARM1, and H3-R17 methylation all precede CBP loading on the MHC-II promoter during IFN-gamma treatment. These results suggest functional and temporal relationships among CIITA, CARM1, and CBP for IFN-gamma induction of MHC-II.
authors.affiliation: Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Zika
authors.forename: Lucas
authors.initials: L
authors.lastname: Fauquier
authors.forename: Laurence
authors.initials: L
authors.lastname: Vandel
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D003345:Corticosterone; D005786:Gene Expression Regulation / Q000187:drug effects*; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics; D059805:HLA-DR alpha-Chains; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008745:Methylation; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D007371:Interferon-gamma; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D003345:Corticosterone