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      Common features of microRNA target prediction tools

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          Abstract

          The human genome encodes for over 1800 microRNAs (miRNAs), which are short non-coding RNA molecules that function to regulate gene expression post-transcriptionally. Due to the potential for one miRNA to target multiple gene transcripts, miRNAs are recognized as a major mechanism to regulate gene expression and mRNA translation. Computational prediction of miRNA targets is a critical initial step in identifying miRNA:mRNA target interactions for experimental validation. The available tools for miRNA target prediction encompass a range of different computational approaches, from the modeling of physical interactions to the incorporation of machine learning. This review provides an overview of the major computational approaches to miRNA target prediction. Our discussion highlights three tools for their ease of use, reliance on relatively updated versions of miRBase, and range of capabilities, and these are DIANA-microT-CDS, miRanda-mirSVR, and TargetScan. In comparison across all miRNA target prediction tools, four main aspects of the miRNA:mRNA target interaction emerge as common features on which most target prediction is based: seed match, conservation, free energy, and site accessibility. This review explains these features and identifies how they are incorporated into currently available target prediction tools. MiRNA target prediction is a dynamic field with increasing attention on development of new analysis tools. This review attempts to provide a comprehensive assessment of these tools in a manner that is accessible across disciplines. Understanding the basis of these prediction methodologies will aid in user selection of the appropriate tools and interpretation of the tool output.

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          Most cited references39

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          Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.

          During C. elegans development, the temporal pattern of many cell lineages is specified by graded activity of the heterochronic gene Lin-14. Here we demonstrate that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4. The lin-14 3'UTR is both necessary and sufficient to confer lin-4-mediated posttranscriptional temporal regulation. The function of the lin-14 3'UTR is conserved between C. elegans and C. briggsae. Among the conserved sequences are seven elements that are each complementary to the lin-4 RNAs. A reporter gene bearing three of these elements shows partial temporal gradient activity. These data suggest a molecular mechanism for Lin-14p temporal gradient formation: the lin-4 RNAs base pair to sites in the lin-14 3'UTR to form multiple RNA duplexes that down-regulate lin-14 translation.
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            Prediction of mammalian microRNA targets.

            MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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              Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites

              mirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.
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                Author and article information

                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                18 February 2014
                2014
                : 5
                : 23
                Affiliations
                [1] 1Center for Molecular Medicine, Maine Medical Center Research Institute Scarborough, ME, USA
                [2] 2Graduate School of Biomedical Sciences and Engineering, University of Maine Orono, ME, USA
                [3] 3Department of Computer Science, University of Southern Maine Portland, ME, USA
                Author notes

                Edited by: Michael Ochs, The College of New Jersey, USA

                Reviewed by: Subha Madhavan, Georgetown University, USA; Ghislain Bidaut, Institut National de la Santé et de la Recherche Médicale, France; Madhuchhanda Bhattacharjee, University of Hyderabad, India

                *Correspondence: Clare Bates Congdon, Department of Computer Science, University of Southern Maine, 96 Falmouth Street, Portland, ME 04104-9300, USA e-mail: congdon@ 123456usm.maine.edu

                This article was submitted to Bioinformatics and Computational Biology, a section of the journal Frontiers in Genetics.

                Article
                10.3389/fgene.2014.00023
                3927079
                24600468
                ee752275-f908-48bb-a655-ac725690f212
                Copyright © 2014 Peterson, Thompson, Ufkin, Sathyanarayana, Liaw and Congdon.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 November 2013
                : 23 January 2014
                Page count
                Figures: 2, Tables: 11, Equations: 0, References: 60, Pages: 10, Words: 8650
                Categories
                Genetics
                Review Article

                Genetics
                microrna,target prediction,seed match,conservation,free energy,site accessibility,machine learning,computational approaches

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