Parsing the Interferon Transcriptional Network and Its Disease Associations
2016; Cell Press; Volume: 164; Issue: 3 Linguagem: Inglês
10.1016/j.cell.2015.12.032
ISSN1097-4172
AutoresSara Mostafavi, Hideyuki Yoshida, Devapregasan Moodley, Hugo Le Boité, Katherine Rothamel, Towfique Raj, Chun Ye, Nicolas Chevrier, Shen‐Ying Zhang, Ting Feng, Mark N. Lee, Jean‐Laurent Casanova, James D. Clark, Martin Hegen, Jean‐Baptiste Telliez, Nir Hacohen, Philip L. De Jager, Aviv Regev, Diane Mathis, Christophe Benoist,
Tópico(s)Cytokine Signaling Pathways and Interactions
ResumoSummary Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.
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