title: Genomic mapping of the MHC transactivator  CIITA using an integrated ChIP-seq and genetical  genomics approach.
abstract: BACKGROUND
  The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC)class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genome-wide function and relationship with underlying genetic diversity has not been resolved.
  
  
  RESULTS
  We report the first genome-wide ChIP-seq map for CIITA and complement this by mapping inter-individual variation in CIITA expression as a quantitative trait. We analyse CIITA recruitment for pathophysiologically relevant primary human B cells and monocytes, resting and treated with interferon-gamma, in the context of the epigenomic regulatory landscape and DNA-binding proteins associated with the CIITA enhanceosome including RFX, CREB1/ATF1 and NFY. We confirm recruitment to proximal promoter sequences in MHC class II genes and more distally involving the canonical CIITA enhanceosome. Overall, we map 843 CIITA binding intervals involving 442 genes and find 95% of intervals are located outside the MHC and 60% not associated with RFX5 binding. Binding intervals are enriched for genes involved in immune function n and infectious disease with novel loci including major histone gene clusters. Were solve differentially expressed genes associated in trans with a CIITA intronic sequence variant, integrate with CIITA recruitment and show how this is mediated by allele-specific recruitment of NF-kB.
  
  
  CONCLUSIONS
  Our results indicate a broader role for CIITA beyond the MHC involving immune-related genes.We provide new insights into allele-specific regulation of CIITA informative for understanding gene function and disease.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt, Drive, Oxford OX3 7BN, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wong
authors.forename: Wanseon
authors.initials: W
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Humburg
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.forename: Evelyn
authors.initials: E
authors.lastname: Lau
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chan
authors.forename: Katharine
authors.initials: K
authors.lastname: Plant
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D040641:Quantitative Trait Loci; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: C083728:MHC class II transactivator protein; D016328:NF-kappa B; D009687:Nuclear Proteins; D015534:Trans-Activators