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Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA

Bucher, Philipp
Published in Journal of Immunology. 2004, vol. 173, no. 10, p. 6200-6210
Abstract MHC class II (MHC-II) genes are regulated by an enhanceosome complex containing two gene-specific transcription factors, regulatory factor X complex (RFX) and CIITA. These factors assemble on a strictly conserved regulatory module (S-X-X2-Y) found immediately upstream of the promoters of all classical and nonclassical MHC-II genes as well as the invariant chain (Ii) gene. To identify new targets of RFX and CIITA, we developed a computational approach based on the unique and highly constrained architecture of the composite S-Y motif. We identified six novel S'-Y' modules situated far away from the promoters of known human RFX- and CIITA-controlled genes. Four are situated at strategic positions within the MHC-II locus, and two are found within the Ii gene. These S'-Y' modules function as transcriptional enhancers, are bona fide targets of RFX and CIITA in B cells and IFN-gamma-induced cells, and induce broad domains of histone hyperacetylation. These results reveal a hitherto unexpected level of complexity involving long distance control of MHC-II expression by multiple distal regulatory elements.
Keywords AcetylationAcetyltransferases/metabolismAntigens, Differentiation, B-Lymphocyte/genetics/metabolismBase SequenceCell Line, TumorComputational Biology/methodsConserved SequenceDNA-Binding Proteins/metabolism/ physiologyEnhancer Elements, Genetic/ physiologyGene Expression Profiling/methodsGenes, MHC Class IIGenetic Markers/immunologyHistocompatibility Antigens Class II/genetics/metabolismHistone AcetyltransferasesHistones/metabolismHumansInterferon-gamma/physiologyLocus Control Region/ physiologyMolecular Sequence DataNuclear Proteins/metabolism/ physiologyPromoter Regions, GeneticProtein Binding/genetics/immunologyTrans-Activators/metabolism/ physiologyTranscription Factors/metabolism/ physiology
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PMID: 15528357
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