Parsing the Interferon Transcriptional Network and Its Disease Associations

Sara Mostafavi; Hideyuki Yoshida; Devapregasan Moodley; Hugo LeBoité; Katherine Rothamel; Towfique Raj; Chun Jimmie Ye; Nicolas Chevrier; Shen-Ying Zhang; Ting Feng; Mark Lee; Jean-Laurent Casanova; James D Clark; Martin Hegen; Jean-Baptiste Telliez; Nir Hacohen; Philip L De Jager; Aviv Regev; Diane Mathis; Christophe Benoist; Immunological Genome Project Consortium

doi:10.1016/j.cell.2015.12.032

Parsing the Interferon Transcriptional Network and Its Disease Associations

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

Authors

Sara Mostafavi¹, Hideyuki Yoshida², Devapregasan Moodley², Hugo LeBoité², Katherine Rothamel², Towfique Raj³, Chun Jimmie Ye⁴, Nicolas Chevrier⁵, Shen-Ying Zhang⁶, Ting Feng², Mark Lee⁴, Jean-Laurent Casanova⁶, James D Clark⁷, Martin Hegen⁷, Jean-Baptiste Telliez⁷, Nir Hacohen⁴, Philip L De Jager³, Aviv Regev⁴, Diane Mathis⁸, Christophe Benoist⁸; Immunological Genome Project Consortium

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4-Positive T-Lymphocytes / metabolism
Datasets as Topic
Gene Regulatory Networks*
Humans
Interferon Type I / immunology*
Interferon Type I / metabolism*
Janus Kinases / metabolism
Mice
Mice, Inbred C57BL
Receptor, Interferon alpha-beta / metabolism

Substances

Interferon Type I
Receptor, Interferon alpha-beta
Janus Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding