title: Common distal elements orchestrate CIITA isoform-specific expression in multiple cell types.
abstract: Major histocompatibility class II (MHC-II) expression is critical for immune responses and is controlled by the MHC-II transactivator CIITA. CIITA is primarily regulated at the transcriptional level and is expressed from three main promoters with myeloid, lymphoid and interferon (IFN)-γ-treated non-hematopoietic cells using promoters pI, pIII and pIV, respectively. Recent studies in non-hematopoietic cells suggest that a series of distal regulatory elements may be involved in regulating CIITA transcription. To identify distal elements in B cells, a DNase I hypersensitivity screen was performed, revealing a series of potential novel regulatory elements. These elements were analyzed computationally and biochemically. Several regions displayed active histone modifications and/or enhanced expression of a reporter gene. Four of the elements interacted with pIII in B cells. These same four regions were also found to interact with pI in splenic dendritic cells (spDC). Intriguingly, examination of the above interactions in pI-knockout-derived spDC showed a switch to the next available promoter, pIII. Extensive DNA methylation was found at the pI region in B cells, suggesting that this promoter is not accessible in B cells. Thus, CIITA expression is likely mediated in hematopoietic cells by common elements with promoter accessibility having a part in promoter choice.
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lohsen
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Majumder
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Scharer
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Barwick
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Austin
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Zinzow-Kramer
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Boss
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019175:DNA Methylation; D003713:Dendritic Cells / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D008214:Lymphocytes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D022423:Myeloid Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D015534:Trans-Activators; D003850:Deoxyribonuclease I
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