Genome-wide Dissection of MicroRNA Functions and Cotargeting Networks Using Gene Set Signatures

Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
Molecular cell (Impact Factor: 14.02). 04/2010; 38(1):140-53. DOI: 10.1016/j.molcel.2010.03.007
Source: PubMed

ABSTRACT MicroRNAs are emerging as important regulators of diverse biological processes and pathologies in animals and plants. Though hundreds of human microRNAs are known, only a few have known functions. Here, we predict human microRNA functions by using a new method that systematically assesses the statistical enrichment of several microRNA-targeting signatures in annotated gene sets such as signaling networks and protein complexes. Some of our top predictions are supported by published experiments, yet many are entirely new or provide mechanistic insights to known phenotypes. Our results indicate that coordinated microRNA targeting of closely connected genes is prevalent across pathways. We use the same method to infer which microRNAs regulate similar targets and provide the first genome-wide evidence of pervasive cotargeting, in which a handful of "hub" microRNAs are involved in a majority of cotargeting relationships. Our method and analyses pave the way to systematic discovery of microRNA functions.

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Available from: Alexander van Oudenaarden, Sep 27, 2015
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    • "It is now commonly accepted that the regulation of any gene is rarely controlled by a single miRNA. Rather, multiple miRNAs often coordinate to modulate the expression of a gene [45]. It is unlikely that miR-146b is solely responsible for suppressing the target genes we have identified during myogenic differentiation. "
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    ABSTRACT: MicroRNAs are established as crucial modulators of skeletal myogenesis, but our knowledge about their identity and targets remains limited. In this study, we have identified microRNA-146b (miR-146b) as a novel regulator of skeletal myoblast differentiation. Following up on a previous microRNA profiling study, we establish that the expression of miR-146b is up-regulated during myoblast differentiation in vitro and muscle regeneration in vivo. Inhibition of miR-146b led to reduced myoblast differentiation, whereas overexpression of miR-146b enhanced differentiation. Computational prediction combined with gene expression information has revealed candidates for miR-146b targets in muscles. Among them, the expression of Smad4, Notch1, and Hmga2 are significantly suppressed by miR-146b overexpression in myocytes. In addition, expression levels of Smad4, Notch1 and Hmga2 are decreased during myoblast differentiation and muscle regeneration, inversely correlating to the levels of miR-146b. Importantly, inhibition of endogenous miR-146b prevents the down-regulation of Smad4, Notch1 and Hmga2 during differentiation. Furthermore, miR-146b directly targets the microRNA response elements (MREs) in the 3'UTR of those genes as assessed by reporter assays. Reporters with the seed regions of MREs mutated are insensitive to miR-146b, further confirming the specificity of targeting. In conclusion, miR-146b is a positive regulator of myogenic differentiation, possibly acting through multiple targets.
    PLoS ONE 06/2014; 9(6):e100657. DOI:10.1371/journal.pone.0100657 · 3.23 Impact Factor
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    • "In particular, the RNA-Seq procedure and analysis approach we described in this study was instrumental to uncover a role of miR-204 in the control of retinal axon guidance, which was further confirmed by in vivo miR-204 KD and OE in appropriate transgenic lines. A great deal of information on miRNA biology was recently obtained by exploiting microarray-based transcriptome analyses, which were carried out using different strategies (20,21). Our study further highlights the advantages of performing such studies using techniques with much higher resolution over microarrays such as RNA-Seq, in particular in model organisms that have limited microarray platforms available. "
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    Nucleic Acids Research 06/2014; 42(12). DOI:10.1093/nar/gku498 · 9.11 Impact Factor
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    • "MicroRNAs (miRNAs), a class of 20–24 nucleotide small noncoding RNAs, play important roles in post-transcriptional gene regulation by targeting mRNAs for cleavage or repressing translation [1]. Although thousands of miRNAs have been identified, the function of most miRNAs involved in biological networks remains unclear [2]. The miRNAs regulate a wide range of cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. "
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    ABSTRACT: MicroRNAs (miRNAs) interact with their target mRNAs and regulate biological processes at post-transcriptional level. While one miRNA can target many mRNAs, a single mRNA can also be targeted by a set of miRNAs. The targeted mRNAs may be involved in different biological processes that are described by gene ontology (GO) terms. The major challenges involved in analyzing these multitude regulations include identification of the combinatorial regulation of miRNAs as well as determination of the co-functionally-enriched miRNA pairs. The C2Analyzer: Co-target−Co-function Analyzer, is a Perl-based, versatile and user-friendly web tool with online instructions. Based on the hypergeometric analysis, this novel tool can determine whether given pairs of miRNAs are co-functionally enriched. For a given set of GO term(s), it can also identify the set of miRNAs whose targets are enriched in the given GO term(s). Moreover, C2Analyzer can also identify the co-targeting miRNA pairs, their targets and GO processes, which they are involved in. The miRNA−miRNA co-functional relationship can also be saved as a .txt file, which can be used to further visualize the co-functional network by using other software like Cytoscape. C2Analyzer is freely available at
    Genomics Proteomics & Bioinformatics 06/2014; 12(3). DOI:10.1016/j.gpb.2014.03.003
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