Parsing the Interferon Transcriptional Network and Its Disease Associations.

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2016
Journal
Cell
Volume
164
Issue
3
Pages
564-78
Date Published
2016 Jan 28
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2015.12.032
PubMed ID
26824662
PubMed Central ID
PMC4743492
Links
Grant list
R24-AI072073 / AI / NIAID NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
R24 AI072073 / AI / NIAID NIH HHS / United States
RC2-GM093080 / GM / NIGMS NIH HHS / United States