miRTar: an integrated system for identifying miRNA-target interactions in human

BackgroundMicroRNAs (miRNAs) are small non-coding RNA molecules that are ~22-nt-long sequences capable of suppressing protein synthesis. Previous research has suggested that miRNAs regulate 30% or more of the human protein-coding genes. The aim of this work is to consider various analyzing scenarios in the identification of miRNA-target interactions, as well as to provide an integrated system that will aid in facilitating investigation on the influence of miRNA targets by alternative splicing and the biological function of miRNAs in biological pathways.ResultsThis work presents an integrated system, miRTar, which adopts various analyzing scenarios to identify putative miRNA target sites of the gene transcripts and elucidates the biological functions of miRNAs toward their targets in biological pathways. The system has three major features. First, the prediction system is able to consider various analyzing scenarios (1 miRNA:1 gene, 1:N, N:1, N:M, all miRNAs:N genes, and N miRNAs: genes involved in a pathway) to easily identify the regulatory relationships between interesting miRNAs and their targets, in 3'UTR, 5'UTR and coding regions. Second, miRTar can analyze and highlight a group of miRNA-regulated genes that participate in particular KEGG pathways to elucidate the biological roles of miRNAs in biological pathways. Third, miRTar can provide further information for elucidating the miRNA regulation, i.e., miRNA-target interactions, affected by alternative splicing.ConclusionsIn this work, we developed an integrated resource, miRTar, to enable biologists to easily identify the biological functions and regulatory relationships between a group of known/putative miRNAs and protein coding genes. miRTar is now available at http://miRTar.mbc.nctu.edu.tw/.

[1]  Yi-Hsuan Chen,et al.  miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes , 2007, Nucleic Acids Res..

[2]  A. Krainer,et al.  Listening to silence and understanding nonsense: exonic mutations that affect splicing , 2002, Nature Reviews Genetics.

[3]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[4]  Timos K. Sellis,et al.  miRGen 2.0: a database of microRNA genomic information and regulation , 2009, Nucleic Acids Res..

[5]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[6]  David Haussler,et al.  The UCSC Genome Browser database: update 2010 , 2009, Nucleic Acids Res..

[7]  Molly Megraw,et al.  miRGen: a database for the study of animal microRNA genomic organization and function , 2006, Nucleic Acids Res..

[8]  Martin Reczko,et al.  DIANA-mirPath: Integrating human and mouse microRNAs in pathways , 2009, Bioinform..

[9]  Tongbin Li,et al.  miRecords: an integrated resource for microRNA–target interactions , 2008, Nucleic Acids Res..

[10]  Paul Ahlquist,et al.  MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins , 2008, Proceedings of the National Academy of Sciences.

[11]  Reuven Agami,et al.  miR-148 targets human DNMT3b protein coding region. , 2008, RNA.

[12]  Vesselin Baev,et al.  MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence , 2005, Nucleic Acids Res..

[13]  T. Tuschl,et al.  Structure of the guide-strand-containing argonaute silencing complex , 2008, Nature.

[14]  Peter F. Stadler,et al.  Local RNA base pairing probabilities in large sequences , 2006, Bioinform..

[15]  R. Russell,et al.  Principles of MicroRNA–Target Recognition , 2005, PLoS biology.

[16]  Curtis Balch,et al.  MicroRNA and mRNA integrated analysis (MMIA): a web tool for examining biological functions of microRNA expression , 2009, Nucleic Acids Res..

[17]  C. Ghigna,et al.  Alternative Splicing and Tumor Progression , 2008, Current genomics.

[18]  George Easow,et al.  Isolation of microRNA targets by miRNP immunopurification. , 2007, RNA.

[19]  Chi-Ying F. Huang,et al.  miRTarBase: a database curates experimentally validated microRNA–target interactions , 2010, Nucleic Acids Res..

[20]  U. A. Ørom,et al.  MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. , 2008, Molecular cell.

[21]  Sanghyuk Lee,et al.  miRGator: an integrated system for functional annotation of microRNAs , 2007, Nucleic Acids Res..

[22]  Julius Brennecke,et al.  Identification of Drosophila MicroRNA Targets , 2003, PLoS biology.

[23]  Peng Jin,et al.  Physiological identification of human transcripts translationally regulated by a specific microRNA. , 2005, Human molecular genetics.

[24]  Nectarios Koziris,et al.  DIANA-microT web server: elucidating microRNA functions through target prediction , 2009, Nucleic Acids Res..

[25]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[26]  Yvonne Tay,et al.  A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes , 2006, Cell.

[27]  Y. Li,et al.  Incorporating structure to predict microRNA targets. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Xiaowei Wang miRDB: a microRNA target prediction and functional annotation database with a wiki interface. , 2008, RNA.

[29]  Q. Cui,et al.  Principles of microRNA regulation of a human cellular signaling network , 2006, Molecular systems biology.

[30]  Anton J. Enright,et al.  MicroRNA targets in Drosophila , 2003, Genome Biology.

[31]  Colin N. Dewey,et al.  A Genome-Wide Map of Conserved MicroRNA Targets in C. elegans , 2006, Current Biology.

[32]  John Yu,et al.  Human TRIM71 and its nematode homologue are targets of let-7 microRNA and its zebrafish orthologue is essential for development. , 2007, Molecular biology and evolution.

[33]  Konstantinos N. Malizos,et al.  Integrative MicroRNA and Proteomic Approaches Identify Novel Osteoarthritis Genes and Their Collaborative Metabolic and Inflammatory Networks , 2008, PloS one.

[34]  G. Rubin,et al.  A computer program for aligning a cDNA sequence with a genomic DNA sequence. , 1998, Genome research.

[35]  Fei Li,et al.  Abundant conserved microRNA target sites in the 5′-untranslated region and coding sequence , 2009, Genetica.

[36]  BMC Bioinformatics , 2005 .

[37]  R. Place,et al.  MicroRNA-373 induces expression of genes with complementary promoter sequences , 2008, Proceedings of the National Academy of Sciences.

[38]  Gregory D. Schuler,et al.  Database resources of the National Center for Biotechnology Information: update , 2004, Nucleic acids research.

[39]  David L. Wheeler,et al.  GenBank , 2015, Nucleic Acids Res..

[40]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[41]  D. Church,et al.  Spidey: a tool for mRNA-to-genomic alignments. , 2001, Genome research.

[42]  Yuanji Zhang,et al.  miRU: an automated plant miRNA target prediction server , 2005, Nucleic Acids Res..

[43]  Liang Chen,et al.  Studying alternative splicing regulatory networks through partial correlation analysis , 2009, Genome Biology.

[44]  Alexander Souvorov,et al.  Splign: algorithms for computing spliced alignments with identification of paralogs , 2008, Biology Direct.

[45]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[46]  Oliver Hofmann,et al.  ASTD: The Alternative Splicing and Transcript Diversity database. , 2009, Genomics.

[47]  Kristin C. Gunsalus,et al.  microRNA Target Predictions across Seven Drosophila Species and Comparison to Mammalian Targets , 2005, PLoS Comput. Biol..

[48]  J. Castle,et al.  Genome-Wide Survey of Human Alternative Pre-mRNA Splicing with Exon Junction Microarrays , 2003, Science.

[49]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[50]  Susumu Goto,et al.  KEGG for representation and analysis of molecular networks involving diseases and drugs , 2009, Nucleic Acids Res..

[51]  C. Lee,et al.  MicroRNA and cancer – focus on apoptosis , 2008, Journal of cellular and molecular medicine.

[52]  B. Brinkman,et al.  Splice variants as cancer biomarkers. , 2004, Clinical biochemistry.

[53]  Hsien-Da Huang,et al.  miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes , 2005, Nucleic Acids Res..

[54]  Colin N. Dewey,et al.  Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures , 2007, Nature.

[55]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[56]  Jorng-Tzong Horng,et al.  SpliceInfo: an information repository for mRNA alternative splicing in human genome , 2004, Nucleic Acids Res..

[57]  Mihaela Zavolan,et al.  Inference of miRNA targets using evolutionary conservation and pathway analysis , 2007, BMC Bioinformatics.

[58]  Guey-Shin Wang,et al.  Splicing in disease: disruption of the splicing code and the decoding machinery , 2007, Nature Reviews Genetics.

[59]  Dang D. Long,et al.  Potent effect of target structure on microRNA function , 2007, Nature Structural &Molecular Biology.

[60]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[61]  R. Giegerich,et al.  Fast and effective prediction of microRNA/target duplexes. , 2004, RNA.

[62]  A. Kornblihtt,et al.  The connection between splicing and cancer , 2006, Journal of Cell Science.

[63]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[64]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[65]  Georgios Papachristoudis,et al.  Human microRNA target analysis and gene ontology clustering by GOmir, a novel stand-alone application , 2009, BMC Bioinformatics.

[66]  C. Burge,et al.  Most mammalian mRNAs are conserved targets of microRNAs. , 2008, Genome research.

[67]  Joshua J. Forman,et al.  A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence , 2008, Proceedings of the National Academy of Sciences.

[68]  Yvonne Tay,et al.  MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation , 2008, Nature.

[69]  D. Haussler,et al.  Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. , 2005, Genome research.