Identification of <i>cis</i>- and <i>trans</i>-regulatory variation modulating microRNA expression levels in human fibroblasts

Borel, Christelle; Deutsch, Samuel; Letourneau, Audrey; Migliavacca, Eugenia; Montgomery, Stephen B.; Dimas, Antigone S.; Vejnar, Charles E.; Attar, Homa; Gagnebin, Maryline; Gehrig, Corinne; Falconnet, Emilie; Dupré, Yann; Dermitzakis, Emmanouil T.; Antonarakis, Stylianos E.

doi:10.1101/gr.109371.110

Cited by 72 publications

(69 citation statements)

References 33 publications

(42 reference statements)

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“…It is notable that expression levels of miRNAs vary greatly in natural human populations Borel et al 2011). In Supplemental Figure S5, we show that in lymphoblastoid cells of 90 European-American males ), the expressed miRNAs have a very similar distribution of CV as the ;14,000 coexpressed mRNAs-the median CV of miRNAs is 2.75, which is slightly higher than that of mRNAs.…”

Section: Synergistic Effects Of Mirna Regulationmentioning

confidence: 74%

Impact of microRNA regulation on variation in human gene expression

2012

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MicroRNAs (miRNAs) are endogenously expressed small RNAs that regulate expression of mRNAs at the post-transcriptional level. The consequence of miRNA regulation is hypothesized to reduce the expression variation of target genes. However, it is possible that mutations in miRNAs and target sites cause rewiring of the miRNA regulatory networks resulting in increased variation in gene expression. By examining variation in gene expression patterns in human populations and between human and other primate species, we find that miRNAs have stabilized expression of a small number of target genes during primate evolution. Compared with genes not regulated by miRNAs, however, genes regulated by miRNAs overall have higher expression variation at the population level, and they display greater variation in expression among human ethnic groups or between human and other primate species. By integrating expression data with genotypes determined in the HapMap 3 and the 1000 Genomes Projects, we found that expression variation in miRNAs, genetic variants in miRNA loci, and mutations in miRNA target sites are important sources of elevated expression variation of miRNA target genes. A reasonable case can be made that natural selection is driving this pattern of variation.

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Section: Synergistic Effects Of Mirna Regulationmentioning

confidence: 74%

Impact of microRNA regulation on variation in human gene expression

2012

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“…The extent to which this variation is under genetic control (i.e., miRNA expression quantitative trait loci, miR-eQTLs) has recently begun to be investigated (Borel et al 2011;Rantalainen et al 2011;Gamazon et al 2012;Parts et al 2012;Civelek et al 2013;Gamazon et al 2013;Lappalainen et al 2013). However, as has been shown for mRNAs in yeast and mammals, genetic variants can differentially affect gene expression after perturbation by various treatments or environmental variables (i.e., response eQTLs) (Gargalovic et al 2006;Smith and Kruglyak 2008;Smirnov et al 2009;Yang et al 2009;Dombroski et al 2010;Romanoski et al 2010;Maranville et al 2011;Barreiro et al 2012).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

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

et al. 2014

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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.

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“…Studies primarily in blood, skin, liver, adipose, and brain indicate that eQTLs are common in humans [4][5][6] . Genetic variation can also influence gene expression through alterations in splicing, non-coding RNAs, and RNA stability [7][8][9] . eQTLs regulating nearby or distant genes are commonly referred to as ciseQTLs and trans-eQTLs, respectively 3 .…”

mentioning

confidence: 99%

The Genotype-Tissue Expression (GTEx) Project

Carithers

Moore

2015

Biopreservation and Biobanking

461

411

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Genome-wide association studies have identified thousands of loci for common diseases, but for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions are likely to contribute to many disease phenotypes. The careful examination of gene expression and its relationship to genetic variation has thus become a critical next step in the elucidation of the genetic basis of common disease. Cell context is a key determinant of gene regulation; but to date, the challenge of collecting large numbers of diverse tissues in humans has largely precluded such studies outside of a few easily sampled cell types. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.

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Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts

Cited by 72 publications

References 33 publications

Impact of microRNA regulation on variation in human gene expression

Impact of microRNA regulation on variation in human gene expression

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

The Genotype-Tissue Expression (GTEx) Project

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