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Cell. 2016 Jan 28;164(3):564-78. doi: 10.1016/j.cell.2015.12.032.

Parsing the Interferon Transcriptional Network and Its Disease Associations.

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Statistics and Department Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
2
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5
FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
6
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
7
Pfizer Immunosciences, Cambridge, MA 02140, USA.
8
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cbdm@hms.harvard.edu.

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.

PMID:
26824662
PMCID:
PMC4743492
DOI:
10.1016/j.cell.2015.12.032
[Indexed for MEDLINE]
Free PMC Article

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