A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

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.

Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility

“…76 Similar to splicing, miRNA QTLs studies ( Figure 2B) have generally suggested a limited genetic control of miRNAs, consistent with expectation of strong selective constraints on miRNA expression due to their widespread impact on gene expression. 57,76 miRNA QTLs appear to be strongly enriched in variants located at their promoter and eQTLs of their host gene. 77 However, there is also strong evidence that enhancers and loci that are bound by transcription factors contribute to miRNA expression.…”

“…The regulation of miRNA expression has also been extensively studied, both at basal state and in response to infection . Similar to splicing, miRNA QTLs studies (Figure B) have generally suggested a limited genetic control of miRNAs, consistent with expectation of strong selective constraints on miRNA expression due to their widespread impact on gene expression .…”

The human gene damage index as a gene-level approach to prioritizing exome variants

“…Further studies of mutational damage to human genes should include population-specific analyses, as the GDI probably varies with ethnic background and the demographic history of the population (43). It will also be interesting to extend the GDI to the different isoforms of protein-coding genes (44)(45)(46) and noncoding RNAs (47) and to take regulatory variants into account (48). Finally, a consideration of copy number variation would also refine the calculation of the GDI (49).…”

When genetics meets epigenetics: deciphering the mechanisms controlling inter-individual variation in immune responses to infection

“…The integrated epigenetic profiles can then be used as a priori information to help identifying causal SNPs and delineate the mechanistic basis of inter-individual differences in immune response. Although the studies discussed herein have primarily focused on transcriptional responses of coding genes and on innate immunity, we expect in the upcoming years to see the integrative use of in vitro immunological assays with genetic and epigenetic information to be applied to other immunological-related endophenotypes (e.g., stimuli-induced cytokine and chemokine levels [13]), to the study of the genetic regulation of immune-associated microRNAs [65] and long noncoding RNAs, as well as to the study of the mechanistic basis of heterogeneity in adaptive immune responses [11]. Results from these studies will provide a foundation for defining the primary factors leading to perturbations in an individual's immune responses, thus making it possible to devise personalized therapeutic regimes in a more informed manner.…”