Article (Scientific journals)
Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages
Antony, Paul; Tallam, Aravind; Perumal, Thanneer Malai et al.
2016In PLoS ONE
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Abstract :
[en] 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 TNFα and IFNγ, 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.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Computational Biology (Del Sol Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Antony, Paul ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Tallam, Aravind ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Perumal, Thanneer Malai ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Jäger, Christian  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Fritz, Joëlle ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Balling, Rudi ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
del Sol Mesa, Antonio ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Michelucci, Alessandro ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Vallar, Laurent
External co-authors :
yes
Language :
English
Title :
Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages
Publication date :
February 2016
Journal title :
PLoS ONE
ISSN :
1932-6203
Publisher :
Public Library of Science, San Franscisco, United States - California
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
FNR - Fonds National de la Recherche [LU]
Available on ORBilu :
since 08 May 2016

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