Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages

被引:74
作者
Tallam, Aravind [1 ,4 ]
Perumal, Thaneer M. [1 ,5 ]
Antony, Paul M. [1 ]
Jaeger, Christian [1 ]
Fritz, Joelle V. [1 ]
Vallar, Laurent [2 ]
Balling, Rudi [1 ]
del Sol, Antonio [1 ]
Michelucci, Alessandro [1 ,3 ]
机构
[1] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg
[2] Luxembourg Inst Hlth, Genom Res Lab, Luxembourg, Luxembourg
[3] Luxembourg Inst Hlth, NORLUX Neurooncol Lab, Luxembourg, Luxembourg
[4] Zentrum Expt & Klin Infekt Forsch, TWINCORE, Hannover, Germany
[5] Sage Bionetworks, Seattle, WA USA
关键词
NITRIC-OXIDE PRODUCTION; IMMUNE-RESPONSIVE GENE-1; FACTOR-I; IFN-BETA; MYCOBACTERIUM-TUBERCULOSIS; NO SYNTHASE; EXPRESSION; BINDING; PROTEIN; INDUCTION;
D O I
10.1371/journal.pone.0149050
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive gene 1 protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalysing the production of itaconic acid from cis-aconitic acid, a tricarboxylic acid (TCA) cycle intermediate. Itaconic acid possesses specific antimicrobial properties inhibiting isocitrate lyase, the first enzyme of the glyoxylate shunt, an anaplerotic pathway that bypasses the TCA cycle and enables bacteria to survive on limited carbon conditions. To elucidate the mechanisms underlying itaconic acid production through IRG1 induction in macrophages, we examined the transcriptional regulation of IRG1. To this end, we studied IRG1 expression in human immune cells under different inflammatory stimuli, such as TNF alpha and IFN gamma, in addition to lipopolysaccharides. Under these conditions, as previously shown in mouse macrophages, IRG1/CAD accumulates in mitochondria. Furthermore, using literature information and transcription factor prediction models, we re-constructed raw gene regulatory networks (GRNs) for IRG1 in mouse and human macrophages. We further implemented a contextualization algorithm that relies on genome-wide gene expression data to infer putative cell type-specific gene regulatory interactions in mouse and human macrophages, which allowed us to predict potential transcriptional regulators of IRG1. Among the computationally identified regulators, siRNA-mediated gene silencing of interferon regulatory factor 1 (IRF1) in macrophages significantly decreased the expression of IRG1/CAD at the gene and protein level, which correlated with a reduced production of itaconic acid. Using a synergistic approach of both computational and experimental methods, we here shed more light on the transcriptional machinery of IRG1 expression and could pave the way to therapeutic approaches targeting itaconic acid levels.
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页数:28
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