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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Acetyltransferases / metabolism
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Base Sequence
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Cell Line, Tumor
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Computational Biology / methods
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Conserved Sequence
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Enhancer Elements, Genetic / physiology*
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Gene Expression Profiling* / methods
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Genes, MHC Class II*
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Genetic Markers / immunology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism
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Histone Acetyltransferases
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Histones / metabolism
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Humans
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Interferon-gamma / physiology
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Locus Control Region / physiology*
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Molecular Sequence Data
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Promoter Regions, Genetic
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Protein Binding / genetics
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Protein Binding / immunology
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Regulatory Factor X Transcription Factors
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transcription Factors / metabolism
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Transcription Factors / physiology*
Substances
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Antigens, Differentiation, B-Lymphocyte
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DNA-Binding Proteins
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Genetic Markers
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Histocompatibility Antigens Class II
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Histones
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MHC class II transactivator protein
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Nuclear Proteins
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Regulatory Factor X Transcription Factors
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Trans-Activators
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Transcription Factors
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invariant chain
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Interferon-gamma
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Acetyltransferases
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Histone Acetyltransferases