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


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.

Download full-text


Available from: Alexander van Oudenaarden
    • "miR-605 is a PSM that in humans is located within intron 2 of the PRKG1 gene. Interestingly, miR-605 was identified as a member of the p53 network[31]. This miRNA was shown to be transcriptionally activated by p53 and to directly target MDM2, an inhibitor of p53. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The largest proportion of microRNAs in humans (ca. 40-50%) originated in the phylogenetic grouping defined as primates. The dynamic evolution of this family of non-coding RNA is further demonstrated by the presence of microRNA unique to the human species. Investigations into the role of microRNA in cancer have until recently mainly focused on the more ancient members of this RNA family that are widely conserved in the animal kingdom. As I describe in this review the evolutionary young lineage and species-specific microRNA could be important contributors to cancers, especially in particular organs in primates compared to more distantly-related research models. Elucidating the biological significance of primate and human-specific microRNA in cancer could have important implications for cancer research and the use of non-primate animal models.
    No preview · Article · Jan 2016 · BioEssays
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jun 2014 · PLoS ONE
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vertebrate organogenesis is critically sensitive to gene dosage and even subtle variations in the expression levels of key genes may result in a variety of tissue anomalies. MicroRNAs (miRNAs) are fundamental regulators of gene expression and their role in vertebrate tissue patterning is just beginning to be elucidated. To gain further insight into this issue, we analysed the transcriptomic consequences of manipulating the expression of miR-204 in the Medaka fish model system. We used RNA-Seq and an innovative bioinformatics approach, which combines conventional differential expression analysis with the behavior expected by miR-204 targets after its overexpression and knockdown. With this approach combined with a correlative analysis of the putative targets, we identified a wider set of miR-204 target genes belonging to different pathways. Together, these approaches confirmed that miR-204 has a key role in eye development and further highlighted its putative function in neural differentiation processes, including axon guidance as supported by in vivo functional studies. Together, our results demonstrate the advantage of integrating next-generation sequencing and bioinformatics approaches to investigate miRNA biology and provide new important information on the role of miRNAs in the control of axon guidance and more broadly in nervous system development.
    Full-text · Article · Jun 2014 · Nucleic Acids Research
Show more