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

J Immunol. 2004 Nov 15;173(10):6200-10. doi: 10.4049/jimmunol.173.10.6200.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acetyltransferases / metabolism
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Base Sequence
  • Cell Line, Tumor
  • Computational Biology / methods
  • Conserved Sequence
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Enhancer Elements, Genetic / physiology*
  • Gene Expression Profiling* / methods
  • Genes, MHC Class II*
  • Genetic Markers / immunology
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism
  • Histone Acetyltransferases
  • Histones / metabolism
  • Humans
  • Interferon-gamma / physiology
  • Locus Control Region / physiology*
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Regulatory Factor X Transcription Factors
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • DNA-Binding Proteins
  • Genetic Markers
  • Histocompatibility Antigens Class II
  • Histones
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Regulatory Factor X Transcription Factors
  • Trans-Activators
  • Transcription Factors
  • invariant chain
  • Interferon-gamma
  • Acetyltransferases
  • Histone Acetyltransferases