title: A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses.
abstract: Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses and their transcription is regulated by a variety of transcription factors; principal among these is the family of interferon regulatory factors (IRFs). The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Litvak
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ratushny
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Lampano
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitz
authors.forename: Albert C
authors.initials: AC
authors.lastname: Huang
authors.forename: Ayush
authors.initials: A
authors.lastname: Raman
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.forename: John D
authors.initials: JD
authors.lastname: Aitchison
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D000818:Animals; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015203:Reproducibility of Results; D018116:Vesiculovirus / Q000276:immunology*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse