title: Interferon regulatory factor 1 marks activated genes and can induce target gene expression in systemic lupus erythematosus.
abstract: OBJECTIVE
  Interferon regulatory factor 1 (IRF-1) mediates both induction of interferons (IFNs) and responses to type I IFNs. It has been implicated as a critical mediator of inflammation in murine lupus models. In a previous study of chromatin modifications in monocytes from patients with systemic lupus erythematosus (SLE), IRF-1 was implicated as being associated with increased histone acetylation in this disease. The present study was undertaken to directly investigate IRF-1 binding sites on chromatin.
  
  
  METHODS
  Cells from 9 female SLE patients and 7 female controls were examined. Monocytes were purified from peripheral blood and subjected to library preparation using a validated antibody to IRF-1. IRF-1 binding sites on chromatin were identified by chromatin immunoprecipitation followed by sequencing. The effect of IRF-1 on target gene expression was confirmed using an overexpression system in cell lines, and coimmunoprecipitation was used to identify protein interactions.
  
  
  RESULTS
  IRF-1 binding around transcribed regions was increased in SLE patient monocytes, but histone modifications at potential IRF-1 binding sites without detectable IRF-1 binding were increased as well. Overexpression of IRF-1 was sufficient to drive transcription of target genes. IRF-1 overexpression was also able to alter histone modifications at a focus set of target genes, and treatment with an IRF-1 inhibitor reduced both expression and histone modifications at target genes. IRF-1 was found to interact with a select set of histone-modifying enzymes and other transcription factors.
  
  
  CONCLUSIONS
  IRF-1 is an important signaling protein in the interferon pathway. It not only activates gene expression as a transcription factor, but may perpetuate disease by leading to a dysregulated epigenome.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lihua
authors.initials: L
authors.lastname: Shi
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.forename: Elshaddai
authors.initials: E
authors.lastname: Ephrem
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1