[PDF][PDF] Parsing the interferon transcriptional network and its disease associations

S Mostafavi, H Yoshida, D Moodley, H LeBoité… - Cell, 2016 - cell.com
S Mostafavi, H Yoshida, D Moodley, H LeBoité, K Rothamel, T Raj, CJ Ye, N Chevrier
Cell, 2016cell.com
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 …
Summary
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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