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Ago HITS-CLIP decodes miRNA-mRNA interaction maps

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      Summary

      MicroRNAs (miRNAs) play critical roles in the regulation of gene expression. However, since miRNA activity requires base pairing with only 6-8 nucleotides of mRNA, predicting target mRNAs is a major challenge. Recently, high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) has identified functional protein-RNA interaction sites. Here we use HITS-CLIP to covalently crosslink native Argonaute (Ago) protein-RNA complexes in mouse brain. This produced two simultaneous datasets—Ago-miRNA and Ago-mRNA binding sites—that were combined with bioinformatic analysis to identify miRNA-target mRNA interaction sites. We validated genome-wide interaction maps for miR-124, and generated additional maps for the 20 most abundant miRNAs present in P13 mouse brain. Ago HITS-CLIP provides a general platform for exploring the specificity and range of miRNA action in vivo, and identifies precise sequences for targeting clinically relevant miRNA-mRNA interactions.

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      MicroRNAs: genomics, biogenesis, mechanism, and function.

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      MicroRNAs (miRNAs) are endogenous approximately 22 nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
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        Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

        We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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          The functions of animal microRNAs.

           Victor Ambros (2004)
          MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.
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            Author and article information

            Affiliations
            Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Ave, NY, NY 10021 USA
            Author notes

            Author Contributions S.W.C. and R.B.D conceived, designed and supervised the experiments, analyzed the data and wrote the paper. J.B.Z did the initial experiments with the 7G1-1* antibody. A.M. helped with all HITS-CLIP experiments.

            Journal
            0410462
            6011
            Nature
            Nature
            0028-0836
            1476-4687
            13 July 2009
            17 June 2009
            23 July 2009
            23 January 2010
            : 460
            : 7254
            : 479-486
            2733940
            19536157
            10.1038/nature08170
            nihpa120632
            Funding
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: Howard Hughes Medical Institute
            Award ID: R01 NS034389-14 ||NS
            Funded by: National Institute of Neurological Disorders and Stroke : NINDS
            Funded by: Howard Hughes Medical Institute
            Award ID: ||HHMI_
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