PMID- 21216962 OWN - NLM STAT- MEDLINE DCOM- 20110511 LR - 20211020 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 286 IP - 10 DP - 2011 Mar 11 TI - Positive regulatory domain I (PRDM1) and IRF8/PU.1 counter-regulate MHC class II transactivator (CIITA) expression during dendritic cell maturation. PG - 7893-7904 LID - S0021-9258(20)53934-3 [pii] LID - 10.1074/jbc.M110.165431 [doi] AB - Dendritic cells (DCs) are key mediators of immune function through robust and tightly regulated presentation of antigen in the context of the MHC Class II. MHC Class II expression is controlled by the transactivator CIITA. CIITA expression in conventional DCs is uniquely dependent on an uncharacterized myeloid cell-specific promoter, CIITApI. We now identify in vivo the promoter structure and factors regulating CIITApI. In immature DCs transcription requires binding of PU.1, IRF8, NFkappaB, and Sp1 to the promoter. PU.1 binds independently at one site and in a required heterodimer with IRF8 at a composite element. DCs from IRF8-null mice have an unoccupied CIITApI promoter that can be rescued by reconstitution with IRF8 in vitro. Furthermore, mutation of either PU.1 site or the IFR8 site inhibits transcriptional activation. In vivo footprinting and chromatin immunoprecipitation reveals that DC maturation induces complete disassociation of the bound activators paralleled by recruitment of PRDM1/Blimp-1 to the promoter. PRDM1 is a transcriptional repressor with essential roles in B cells, T cells, NK cells, and DCs. We show that PRDM1 co-repressors, G9a and HDAC2, are recruited to CIITApI, leading to a loss of histone acetylation and acquisition of histone H3K9 dimethylation and heterochromatin protein 1gamma (HP1gamma). PRDM1 binding also blocks IRF8-mediated activation dependent on the PU.1/IRF composite element. Together these findings reveal the mechanisms regulating CIITA and, thus, antigen presentation in DCs, demonstrating that PRDM1 and IRF8/PU.1 counter-regulate expression. The activity of PRDM1 in silencing all three cell type-specific CIITA promoters places it as a central regulator of antigen presentation. FAU - Smith, Matthew A AU - Smith MA AD - From the H. Lee Moffitt Cancer Center and Research Institute, Department of Molecular Medicine and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612. FAU - Wright, Gabriela AU - Wright G AD - From the H. Lee Moffitt Cancer Center and Research Institute, Department of Molecular Medicine and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612. FAU - Wu, Jian AU - Wu J AD - From the H. Lee Moffitt Cancer Center and Research Institute, Department of Molecular Medicine and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612. FAU - Tailor, Prafullakumar AU - Tailor P AD - the Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bethesda, Maryland 20892. FAU - Ozato, Keiko AU - Ozato K AD - the Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bethesda, Maryland 20892. FAU - Chen, Xianghong AU - Chen X AD - From the H. Lee Moffitt Cancer Center and Research Institute, Department of Molecular Medicine and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612. FAU - Wei, Sheng AU - Wei S AD - From the H. Lee Moffitt Cancer Center and Research Institute, Department of Molecular Medicine and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612. FAU - Piskurich, Janet F AU - Piskurich JF AD - the Department of Medical Education, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas 79905, and. FAU - Ting, Jenny P-Y AU - Ting JP AD - the Department of Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599. FAU - Wright, Kenneth L AU - Wright KL AD - From the H. Lee Moffitt Cancer Center and Research Institute, Department of Molecular Medicine and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612,. Electronic address: ken.wright@moffitt.org. LA - eng GR - R01 CA114504-05/CA/NCI NIH HHS/United States GR - R01 CA080990/CA/NCI NIH HHS/United States GR - CA080990/CA/NCI NIH HHS/United States GR - R37 AI029564/AI/NIAID NIH HHS/United States GR - R56 AI029564/AI/NIAID NIH HHS/United States GR - R01 CA114504/CA/NCI NIH HHS/United States GR - AI029564/AI/NIAID NIH HHS/United States GR - P30 CA076292/CA/NCI NIH HHS/United States GR - R01 AI029564/AI/NIAID NIH HHS/United States GR - CA114504/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110107 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Histocompatibility Antigens) RN - 0 (Histones) RN - 0 (Interferon Regulatory Factors) RN - 0 (MHC class II transactivator protein) RN - 0 (Nuclear Proteins) RN - 0 (Prdm1 protein, mouse) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Repressor Proteins) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 0 (interferon regulatory factor-8) RN - 0 (proto-oncogene protein Spi-1) RN - 138415-26-6 (PRDM1 protein, human) RN - EC 2.1.1.- (Positive Regulatory Domain I-Binding Factor 1) RN - EC 2.1.1.43 (EHMT2 protein, human) RN - EC 2.1.1.43 (G9a protein, mouse) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 3.5.1.98 (HDAC2 protein, human) RN - EC 3.5.1.98 (Hdac2 protein, mouse) RN - EC 3.5.1.98 (Histone Deacetylase 2) SB - IM MH - Acetylation MH - Animals MH - Antigen Presentation/*physiology MH - Dendritic Cells/cytology/immunology/*metabolism MH - Histocompatibility Antigens/genetics/immunology/metabolism MH - Histone Deacetylase 2/genetics/immunology/metabolism MH - Histone-Lysine N-Methyltransferase/genetics/immunology/metabolism MH - Histones/genetics/immunology/metabolism MH - Humans MH - Interferon Regulatory Factors/genetics/immunology/*metabolism MH - Mice MH - Mice, Knockout MH - Nuclear Proteins/genetics/immunology/*metabolism MH - Positive Regulatory Domain I-Binding Factor 1 MH - Protein Structure, Tertiary MH - Proto-Oncogene Proteins/genetics/immunology/*metabolism MH - Repressor Proteins/genetics/immunology/*metabolism MH - Response Elements/physiology MH - Trans-Activators/genetics/immunology/*metabolism MH - Transcription Factors/genetics/immunology/*metabolism MH - Transcription, Genetic/physiology PMC - PMC3048676 EDAT- 2011/01/11 06:00 MHDA- 2011/05/12 06:00 PMCR- 2012/03/11 CRDT- 2011/01/11 06:00 PHST- 2011/01/11 06:00 [entrez] PHST- 2011/01/11 06:00 [pubmed] PHST- 2011/05/12 06:00 [medline] PHST- 2012/03/11 00:00 [pmc-release] AID - S0021-9258(20)53934-3 [pii] AID - M110.165431 [pii] AID - 10.1074/jbc.M110.165431 [doi] PST - ppublish SO - J Biol Chem. 2011 Mar 11;286(10):7893-7904. doi: 10.1074/jbc.M110.165431. Epub 2011 Jan 7.