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      Visualization and Analysis of MicroRNAs within KEGG Pathways using VANESA

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          Abstract

          MicroRNAs (miRNAs) are small RNA molecules which are known to take part in post-transcriptional regulation of gene expression. Here, VANESA, an existing platform for reconstructing, visualizing, and analysis of large biological networks, has been further expanded to include all experimentally validated human miRNAs available within miRBase, TarBase and miRTarBase. This is done by integrating a custom hybrid miRNA database to DAWIS-M.D., VANESA’s main data source, enabling the visualization and analysis of miRNAs within large biological pathways such as those found within the Kyoto Encyclopedia of Genes and Genomes (KEGG). Interestingly, 99.15 % of human KEGG pathways either contain genes which are targeted by miRNAs or harbor them. This is mainly due to the high number of interaction partners that each miRNA could have (e.g.: hsa-miR-335-5p targets 2544 genes and 71 miRNAs target NUFIP2). We demonstrate the usability of our system by analyzing the measles virus KEGG pathway as a proof-of-principle model and further highlight the importance of integrating miRNAs (both experimentally validated and predicted) into biological networks for the elucidation of novel miRNA-mRNA interactions of biological importance.

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          Most cited references15

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          Switching from repression to activation: microRNAs can up-regulate translation.

          AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3' untranslated regions (3'UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation-related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA miRcxcr4-likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.
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            MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation.

            MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3' untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3' untranslated region.
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              MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation.

              MicroRNAs (miRNAs) are small RNAs that function as posttranscriptional regulators of gene expression. miRNAs affect a variety of signaling pathways, and impaired miRNA regulation may contribute to the development of cancer and other diseases. Here we show that miRNA miR-10a interacts with the 5' untranslated region of mRNAs encoding ribosomal proteins to enhance their translation. miR-10a alleviates translational repression of the ribosomal protein mRNAs during amino acid starvation and is required for their translational induction following anisomycin treatment or overexpression of RAS. We show that miR-10a binds immediately downstream of the regulatory 5'TOP motif and that the 5'TOP regulatory complex and miR-10a are functionally interconnected. The results show that miR-10a may positively control global protein synthesis via the stimulation of ribosomal protein mRNA translation and ribosome biogenesis and hereby affect the ability of cells to undergo transformation.
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                Author and article information

                Contributors
                Journal
                J Integr Bioinform
                J Integr Bioinform
                jib
                jib
                jib
                Journal of Integrative Bioinformatics
                De Gruyter
                1613-4516
                13 June 2017
                March 2017
                : 14
                : 1
                : 20160004
                Affiliations
                universityNDAL, Bogazici University , deptFaculty of Science, Department of Molecular Biology and Genetics , 34342 Istanbul, Turkey
                Izmir Institute of Technology, Faculty of Science, Department of Molecular Biology and Genetics , 35430 Urla, Izmir, Turkey
                universityBielefeld University , deptFaculty of Technology, Department of Bioinformatics and Medical Informatics , D-33501 Bielefeld, Germany
                Hamid Hamzeiy and Rabia Suluyayla: These authors contributed equally to this work.
                Article
                jib-2016-0004
                10.1515/jib-2016-0004
                6042802
                28609293
                19bcc550-1278-4784-b0d6-e8ecb19b87a5
                ©2017, Jens Allmer, published by De Gruyter, Berlin/Boston

                This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

                History
                : 28 November 2016
                : 3 February 2017
                : 16 February 2017
                Page count
                Figures: 5, Tables: 1, References: 35, Pages: 9
                Categories
                Article

                vanesa,microrna,kegg pathway,target database,measles
                vanesa, microrna, kegg pathway, target database, measles

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