title: Properties of STAT1 and IRF1 enhancers and the influence of SNPs.
abstract: STAT1 and IRF1 collaborate to induce interferon-γ (IFNγ) stimulated genes (ISGs), but the extent to which they act alone or together is unclear. The effect of single nucleotide polymorphisms (SNPs) on in vivo binding is also largely unknown.
  
  
  
  We show that IRF1 binds at proximal or distant ISG sites twice as often as STAT1, increasing to sixfold at the MHC class I locus. STAT1 almost always bound with IRF1, while most IRF1 binding events were isolated. Dual binding sites at remote or proximal enhancers distinguished ISGs that were responsive to IFNγ versus cell-specific resistant ISGs, which showed fewer and mainly single binding events. Surprisingly, inducibility in one cell type predicted ISG-responsiveness in other cells. Several dbSNPs overlapped with STAT1 and IRF1 binding motifs, and we developed methodology to rapidly assess their effects. We show that in silico prediction of SNP effects accurately reflects altered binding both in vitro and in vivo.
  
  
  
  These data reveal broad cooperation between STAT1 and IRF1, explain cell type specific differences in ISG-responsiveness, and identify genetic variants that may participate in the pathogenesis of immune disorders.
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.|Clinical Chemistry Division, Provincial Laboratory Services, Queen Elizabeth Hospital, Charlottetown, PE, Canada.|Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abou El Hassan
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Huang
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Manoja B K
authors.initials: MB
authors.lastname: Eswara
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Aubry
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.|Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Zuyao
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Izzy
authors.initials: I
authors.lastname: Livne-Bar
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Monika
authors.initials: M
authors.lastname: Sangwan
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Ahmad
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, ON, Canada. bremner@lunenfeld.ca.|Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. bremner@lunenfeld.ca.|Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada. bremner@lunenfeld.ca.
authors.forename: Rod
authors.initials: R
authors.lastname: Bremner
mesh_terms: D004742:Enhancer Elements, Genetic; D005805:Genes, MHC Class I; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology*; D008912:Minor Histocompatibility Loci; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma