title: Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation.
abstract: The class II transactivator (CIITA) is a master transcriptional regulator of major histocompatibility complex class II (MHC-II) promoters. CIITA does not bind DNA, but it interacts with the transcription factors RFX5, NF-Y, and CREB and associated chromatin-modifying enzymes to form an enhanceosome. This report examines the effects of histone deacetylases 1 and 2 (HDAC1/HDAC2) on MHC-II gene induction by gamma interferon (IFN-gamma) and CIITA. The results show that an inhibitor of HDACs, trichostatin A, enhances IFN-gamma-induced MHC-II expression, while HDAC1/HDAC2 inhibits IFN-gamma- and CIITA-induced MHC-II gene expression. mSin3A, a corepressor of HDAC1/HDAC2, is important for this inhibition, while NcoR, a corepressor of HDAC3, is not. The effect of this inhibition is directed at CIITA, since HDAC1/HDAC2 reduces transactivation by a GAL4-CIITA fusion protein. CIITA binds to overexpressed and endogenous HDAC1, suggesting that HDAC and CIITA may affect each other by direct or indirect association. Inhibition of HDAC activity dramatically increases the association of NF-YB and RFX5 with CIITA, the assembly of CIITA, NF-YB, and RFX5 enhanceosome, and the extent of H3 acetylation at the MHC-II promoter. These results suggest a model where HDAC1/HDAC2 affect the function of CIITA through a disruption of MHC-II enhanceosome and relevant coactivator-transcription factor association and provide evidence that CIITA may act as a molecular switch to modulate MHC-II transcription by coordinating the functions of both histone acetylases and HDACs.
authors.affiliation: Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Zika
authors.forename: Susanna F
authors.initials: SF
authors.lastname: Greer
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Zhu
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000107:Acetylation; D000818:Animals; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005802:Genes, MHC Class II / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D046911:Macromolecular Substances; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D011401:Promoter Regions, Genetic / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D023081:CCAAT-Binding Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C083728:MHC class II transactivator protein; D046911:Macromolecular Substances; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; C093524:RFX5 protein, human; D011993:Recombinant Fusion Proteins; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D015534:Trans-Activators; D014157:Transcription Factors; C012589:trichostatin A; D007371:Interferon-gamma; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex