Parsing the Interferon Transcriptional Network and Its Disease Associations

被引：247

作者：

Mostafavi, Sara ^{[1
,2
,3
]}

Yoshida, Hideyuki ^{[1
]}

Moodley, Devapregasan ^{[1
]}

LeBoite, Hugo ^{[1
]}

Rothamel, Katherine ^{[1
]}

Raj, Towfique ^{[4
,6
,7
]}

Ye, Chun Jimmie ^{[4
]}

Chevrier, Nicolas ^{[5
]}

Zhang, Shen-Ying ^{[8
]}

Feng, Ting ^{[1
]}

Lee, Mark ^{[4
]}

Casanova, Jean-Laurent ^{[8
]}

Clark, James D. ^{[9
]}

Hegen, Martin ^{[9
]}

Telliez, Jean-Baptiste ^{[9
]}

Hacohen, Nir ^{[4
]}

De Jager, Philip L. ^{[4
,6
,7
]}

Regev, Aviv ^{[4
]}

Mathis, Diane ^{[1
]}

Benoist, Christophe ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA

[2] Univ British Columbia, Dept Stat, Vancouver, BC V6H 3N1, Canada

[3] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA

[6] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, 75 Francis St, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Dept Psychiat, Program Translat NeuroPsychiat Genom, 75 Francis St, Boston, MA 02115 USA

[8] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA

[9] Pfizer Immunosci, Cambridge, MA 02140 USA

来源：

CELL | 2016年 / 164卷 / 03期

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; I INTERFERON; GENE-EXPRESSION; TYK2; ACTIVATION; AUTOIMMUNE; DISCOVERY; RESPONSES; IMMUNITY;

D O I：

10.1016/j.cell.2015.12.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：564 / 578

页数：15

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