Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 4, Pages 585-603Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151764
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Funding
- National Institutes of Health (National Institute of Allergy and Infectious Disease) [R01AI035237]
- James McGill Professorship
- Fonds de Recherche du Quebec Sante
- Canadian Institutes of Health Research Neuroinflammation Training Program
- McGill Integrated Cancer Research Training Program
- Canadian Institutes of Health Research [301538, 232519]
- Human Frontiers Science Program [CDA-00025/2012]
- Canada Research Chairs Program [950-228993]
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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-gamma (IFN-gamma). 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 in IRF8 and IRF1 mutant 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-gamma 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.
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