title: Parsing the Interferon Transcriptional Network and Its Disease Associations.
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.
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Mostafavi
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Devapregasan
authors.initials: D
authors.lastname: Moodley
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: LeBoité
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Rothamel
authors.affiliation: 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.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Chun Jimmie
authors.initials: CJ
authors.lastname: Ye
authors.affiliation: FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chevrier
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Feng
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lee
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Pfizer Immunosciences, Cambridge, MA 02140, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.affiliation: Pfizer Immunosciences, Cambridge, MA 02140, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Hegen
authors.affiliation: Pfizer Immunosciences, Cambridge, MA 02140, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.affiliation: 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.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cbdm@hms.harvard.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cbdm@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D066264:Datasets as Topic; D053263:Gene Regulatory Networks; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D053612:Janus Kinases
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6680-5
references.pmid: 11390995
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11594-9
references.pmid: 14500783
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: Br J Haematol. 1998 Jun;101(3):446-9
references.pmid: 9633884
references.citation: J Biochem Mol Biol. 2004 Nov 30;37(6):635-41
references.pmid: 15607020
references.citation: Annu Rev Immunol. 2005;23:307-36
references.pmid: 15771573
references.citation: J Immunol. 2006 Apr 15;176(8):5078-83
references.pmid: 16585605
references.citation: Immunity. 2006 Sep;25(3):361-72
references.pmid: 16979568
references.citation: Mol Cell. 2006 Dec 8;24(5):747-57
references.pmid: 17157257
references.citation: Science. 2007 Mar 2;315(5816):1274-8
references.pmid: 17332413
references.citation: Nat Immunol. 2008 Oct;9(10):1091-4
references.pmid: 18800157
references.citation: J Comput Biol. 2009 Feb;16(2):279-90
references.pmid: 19193146
references.citation: Cell. 2009 Jul 10;138(1):114-28
references.pmid: 19596239
references.citation: Science. 2009 Oct 9;326(5950):257-63
references.pmid: 19729616
references.citation: PLoS Comput Biol. 2009 Dec;5(12):e1000616
references.pmid: 20019805
references.citation: Cell. 2010 Apr 30;141(3):432-45
references.pmid: 20434984
references.citation: BMC Genomics. 2010;11:199
references.pmid: 20338026
references.citation: Bioinformatics. 2010 Jul 15;26(14):1759-65
references.pmid: 20507895
references.citation: Nature. 2010 Aug 19;466(7309):973-7
references.pmid: 20725040
references.citation: Cell. 2011 Aug 19;146(4):621-32
references.pmid: 21854986
references.citation: Arthritis Res Ther. 2011;13(2):R63
references.pmid: 21496236
references.citation: Cell. 2011 Nov 11;147(4):853-67
references.pmid: 22078882
references.citation: Immunity. 2012 Feb 24;36(2):166-74
references.pmid: 22365663
references.citation: Immunity. 2012 Apr 20;36(4):503-14
references.pmid: 22520844
references.citation: Genes Dev. 2012 May 1;26(9):933-44
references.pmid: 22549956
references.citation: Immunol Cell Biol. 2012 May;90(5):520-7
references.pmid: 22491066
references.citation: Immunity. 2012 Jul 27;37(1):158-70
references.pmid: 22705104
references.citation: Inflamm Res. 2012 Sep;61(9):949-54
references.pmid: 22592861
references.citation: Nat Rev Genet. 2012 Oct;13(10):720-31
references.pmid: 22986266
references.citation: Nat Immunol. 2013 Sep;14(9):901-7
references.pmid: 23872679
references.citation: Nat Methods. 2013 Dec;10(12):1213-8
references.pmid: 24097267
references.citation: Nat Rev Immunol. 2014 Jan;14(1):36-49
references.pmid: 24362405
references.citation: Science. 2014 Mar 7;343(6175):1246980
references.pmid: 24604203
references.citation: Annu Rev Immunol. 2014;32:513-45
references.pmid: 24555472
references.citation: Science. 2014 May 2;344(6183):519-23
references.pmid: 24786080
references.citation: Arthritis Rheumatol. 2014 Jun;66(6):1583-95
references.pmid: 24644022
references.citation: J Med Chem. 2014 Jun 26;57(12):5023-38
references.pmid: 24417533
references.citation: Science. 2014 Sep 12;345(6202):1254665
references.pmid: 25214635
references.citation: Arthritis Rheumatol. 2014 Nov;66(11):2924-37
references.pmid: 25047021
references.citation: Transl Res. 2015 Feb;165(2):296-305
references.pmid: 25468480
references.citation: Curr Opin Immunol. 2015 Feb;32:7-12
references.pmid: 25463593
references.citation: Science. 2015 Mar 6;347(6226):1259038
references.pmid: 25745177