Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA.
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.
Krawczyk
Michal
M
University of Geneva Medical School, Centre Médical Universitaire, 1 rue Michel-Servet, CH-1211 Geneva, Switzerland.
Peyraud
Nicolas
N
Rybtsova
Natalia
N
Masternak
Krzysztof
K
Bucher
Philipp
P
Barras
Emmanuèle
E
Reith
Walter
W
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D005802:Genes, MHC Class II; D005819:Genetic Markers / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D019901:Locus Control Region / Q000502:physiology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D000944:Antigens, Differentiation, B-Lymphocyte; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D000949:Histocompatibility Antigens Class II; D006657:Histones; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; C045084:invariant chain; D007371:Interferon-gamma; D000123:Acetyltransferases; D051548:Histone Acetyltransferases