Characterizing the role of miRNAs within gene regulatory networks using integrative genomics techniques

Su, Wan-Lin; Kleinhanz, Robert; Schadt, Eric E.

doi:10.1038/msb.2011.23

Cited by 69 publications

(63 citation statements)

References 45 publications

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“…We first showed that the expression of 3% of miRNAs is explained by proximate genetic factors, consistent with several previous estimates (Rantalainen et al 2011;Parts et al 2012;Civelek et al 2013). That 9% of protein-coding genes harbor cis-regulatory variants in the same samples, at an FDR of only 0.01 (Barreiro et al 2012), supports the notion that miRNA expression is under less genetic control than that of mRNAs (Su et al 2011;Civelek et al 2013;Lappalainen et al 2013). The fewer eQTLs detected for miRNAs may reflect a lower permissibility of large changes in their expression, because these would have extensive consequences on the multiple genes and pathways with which miRNAs are associated.…”

Section: Discussionsupporting

confidence: 89%

“…This observation is consistent with the fact that miRNAs are often involved in incoherent feed-forward loops and other complex network relationships with their targets (Hornstein and Shomron 2006;Tsang et al 2007;Vasudevan et al 2007;Martinez et al 2008;Ebert and Sharp 2012;Lu and Clark 2012). The majority of significant miRNA-mRNA correlations in both conditions were accounted for by a small number of miRNAs, as previously observed (Nunez-Iglesias et al 2010;Su et al 2011;Gamazon et al 2012). Upon infection, 46 miRNAs were each correlated with at least 10 mRNAs, of which 15 were found to be associated with over 100 mRNAs and cumulatively accounted for 75% of all significant correlations ( Fig.…”

Section: à7supporting

confidence: 90%

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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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Section: Discussionsupporting

confidence: 89%

Section: à7supporting

confidence: 90%

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

et al. 2014

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“…However, it is not clear whether miRNAs regulate disease-relevant modules of genes in other diseases. A problem with therapeutic intervention may be that multiple miRNAs act synergistically to regulate the same genes (Tsang et al 2010;Ulitsky et al 2010;Sass et al 2011;Su et al 2011;Gennarino et al 2012). This suggests that targeting of multiple miRNAs may be required for therapeutic purposes.…”

Section: Introductionmentioning

confidence: 99%

“…Such manipulations could be further facilitated if there were a few disease-associated miRNAs that acted not only complementarily but also as hubs, which regulate very large numbers of disease-associated mRNAs. Hub miRNAs have been recently described under normal physiological conditions in the mouse (Su et al 2011), in which a small portion of all miRNAs each regulated thousands of mRNAs. It is, however, not clear if there are disease-associated hub miRNAs.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases

Chavali

Bruhn

Tiemann

et al. 2013

RNA

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MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.

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“…miR-182-5p modulates PARP inhibitor sensitivity by targeting multiple components of the DNA repair pathway miR-182-5p has recently been reported to target BRCA1 (Moskwa et al 2011), a critical component of the homologous recombination (HR) pathway, in breast cancer cell lines. Since it has been shown that some miRNAs concurrently target functionally related genes to drive a specific biological signal Tsang et al 2010;Ulitsky et al 2010;Su et al 2011) and miR-182-5p targets are enriched for genes involved in DNA damage repair, we hypothesized that miR-182-5p's action on the HR pathway extends beyond the targeting of BRCA1. miR-182-5p targeting of CHEK2, an upstream regulator of BRCA1, should also alter sensitivity to the HR-mediated repair.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of miRNAs in tumour biology

Krishnan¹

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MicroRNAs are non-coding, negative regulators of gene expression which act either by repressing protein translation or via mRNA degradation. They have been shown to play biologically significant roles in various processes like cell differentiation, proliferation, apoptosis and development in humans as well as other model organisms.miRNAs direct the wide repertoire of normal biological processes by down-regulating the expression of their target genes. Deregulation of miRNAs has been shown to be associated with various human diseases such as cancer. Although several oncomirs have been identified to date, functional studies to understand their mode of action have been hampered by the lack of tools to accurately predict and validate the gene networks repressed. This thesis aims to address this issue by using a combination of highthroughput technologies and subsequent experimental validation using cell based assays.Chapter two takes a closer look at miR-182, which at the time this study was initiated was shown to be deregulated in several cancers, but its biological role and target networks in the context of breast cancer was relatively unknown. We used biotinylated synthetic miRNA to pull-down its endogenous mRNA targets to reveal that it disrupts key pathways underlying tumorigenesis, and subsequently confirmed its clinical relevance in human breast cancers. Chapter three takes a similar approach to identify the biologically relevant targets of miR-139, a novel breast cancer oncomir. The role of miR-139 is more akin to being a potential tumour suppressor supporting our data and published datasets where its expression is frequently downregulated in human breast cancers. In Chapter four, we take a more global approach where using next-generation sequencing technology we identify miRNAs which show dynamic expression across various phases of the cell cycle, another biological process typically disrupted during tumorigenesis. Using online datasets, we try to identify if there is a significant correlation between these oscillating miRNAs and cancer, and also possible regulators of their expression.These approaches facilitate the identification of novel oncomirs and subsequent characterization of their biologically relevant targets using context-dependent cell ii models. In addition these studies show that these miRNAs achieve their functional output by targeting multiple genes, which belong to the same pathway, adding to the existing notion of concomitant suppression. Together, this leads to a better understanding of the miRNA-mediated disruption to specific molecular processes underlying tumorigenesis.Such studies are imperative to explore the potential of oncomirs as possible prognostic, diagnostic or therapeutic tools.

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Characterizing the role of miRNAs within gene regulatory networks using integrative genomics techniques

Abstract: By integrating genotype information, microRNA transcript abundances and mRNA expression levels, Eric Schadt and colleagues provide insights into the genetic basis of microRNA gene expression and the role of microRNAs within the liver gene-regulatory network.

Cited by 69 publications

References 45 publications

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

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

MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases

Functional characterization of miRNAs in tumour biology

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