title: The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation.
abstract: IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by proinflammatory signals such as interferon-γ (IFN-γ). Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type and inIRF8andIRF1mutant primary macrophages to systematically catalog all of the genes bound by (cistromes) and transcriptionally activated by (regulomes) IRF8, IRF1, PU.1, and STAT1, including modulation of epigenetic histone marks. Of the seven binding combinations identified, two (cluster 1 [IRF8/IRF1/STAT1/PU.1] and cluster 5 [IRF1/STAT1/PU.1]) were found to have a major role in controlling macrophage transcriptional programs both at the basal level and after IFN-γ activation. They direct the expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and antimicrobial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immunodeficiencies and with loci associated with several inflammatory diseases in humans.
authors.affiliation: Department of Biochemistry, McGill University, H3G 0B1 Montreal, Quebec, Canada Complex Traits Group, McGill University, H3G 0B1 Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: Sainte Justine Hospital Research Centre, H3T 1C5 Montreal, Quebec, Canada Department of Pediatrics, Faculty of Medicine, University of Montreal, H3T 1J4 Montreal, Quebec, Canada.
authors.forename: Luis B
authors.initials: LB
authors.lastname: Barreiro
authors.affiliation: Department of Biochemistry, McGill University, H3G 0B1 Montreal, Quebec, Canada Complex Traits Group, McGill University, H3G 0B1 Montreal, Quebec, Canada philippe.gros@mcgill.ca.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D002908:Chronic Disease; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014158:Transcription, Genetic / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000099185:Interferon Regulatory Factor-8
chemical_list: D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse