A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection
- Katherine J. Siddle1,2,11,
- Matthieu Deschamps1,2,3,11,
- Ludovic Tailleux4,
- Yohann Nédélec5,6,
- Julien Pothlichet1,2,
- Geanncarlo Lugo-Villarino7,8,
- Valentina Libri9,
- Brigitte Gicquel4,
- Olivier Neyrolles7,8,
- Guillaume Laval1,2,
- Etienne Patin1,2,
- Luis B. Barreiro6,10 and
- Lluís Quintana-Murci1,2,12
- 1Institut Pasteur, Unit of Human Evolutionary Genetics, 75015 Paris, France;
- 2Centre National de la Recherche Scientifique, CNRS URA3012, 75015 Paris, France;
- 3Université Pierre et Marie Curie, Cellule Pasteur UPMC, 75015 Paris, France;
- 4Institut Pasteur, Unit of Mycobacterial Genetics, 75015 Paris, France;
- 5Department of Biochemistry, Faculty of Medicine, University of Montréal, Montréal H3T 1C5, Canada;
- 6Ste-Justine Hospital Research Centre, Montréal H3T 1C5, Canada;
- 7Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France;
- 8Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France;
- 9Institut Pasteur, Centre d’Immunologie Humaine, 75015 Paris, France;
- 10Department of Paediatrics, Faculty of Medicine, University of Montréal, Montréal H3T 1C5, Canada
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↵11 These authors contributed equally to this work.
Abstract
MicroRNAs (miRNAs) are critical regulators of gene expression, and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. Consistent with their diverse functional effects, miRNA expression is highly context dependent and shows marked changes upon cellular activation. However, the genetic control of miRNA expression in response to external stimuli and the impact of such perturbations on miRNA-mediated regulatory networks at the population level remain to be determined. Here we assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped expression quantitative trait loci (eQTL) in dendritic cells from a panel of healthy individuals. Genome-wide expression profiling revealed that ∼40% of miRNAs are differentially expressed upon infection. We find that the expression of 3% of miRNAs is controlled by proximate genetic factors, which are enriched in a promoter-specific histone modification associated with active transcription. Notably, we identify two infection-specific response eQTLs, for miR-326 and miR-1260, providing an initial assessment of the impact of genotype-environment interactions on miRNA molecular phenotypes. Furthermore, we show that infection coincides with a marked remodeling of the genome-wide relationships between miRNA and mRNA expression levels. This observation, supplemented by experimental data using the model of miR-29a, sheds light on the role of a set of miRNAs in cellular responses to infection. Collectively, this study increases our understanding of the genetic architecture of miRNA expression in response to infection, and highlights the wide-reaching impact of altering miRNA expression on the transcriptional landscape of a cell.
Footnotes
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↵12 Corresponding author
E-mail quintana{at}pasteur.fr
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.161471.113.
- Received June 3, 2013.
- Accepted January 22, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
