Bioinformatics Methods for Studying MicroRNA and ARE-Mediated Regulation of Post-Transcriptional Gene Expression

MicroRNAs (miRNAs) are short single-stranded RNA molecules with 21-22 nucleotides known to regulate post-transcriptional expression of protein-coding genes involved in most of the cellular processes. Prediction of miRNA targets is a challenging bioinformatics problem. AU-rich elements (AREs) are regulatory RNA motifs found in the 3’ untranslated regions (UTRs) of mRNAs, and they play dominant roles in the regulated decay of short-lived human mRNAs via specific interactions with proteins. In this paper, the authors review several miRNA target prediction tools and data sources, as well as computational methods used for the prediction of AREs. The authors discuss the connection between miRNA and ARE-mediated post-transcriptional gene regulation. Finally, a data mining method for identifying the co-occurrences of miRNA target sites in ARE containing genes is presented.

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

[2]  P. Anderson,et al.  Regulation of Cyclooxygenase-2 Expression by the Translational Silencer TIA-1 , 2003, The Journal of experimental medicine.

[3]  Lena Smirnova,et al.  The FASEB Journal • Research Communication Post-transcriptional regulation of the let-7 microRNA during neural cell specification , 2022 .

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

[5]  I. Gallouzi,et al.  Decoding ARE-mediated decay: is microRNA part of the equation? , 2008, The Journal of cell biology.

[6]  E. Espel.  The role of the AU-rich elements of mRNAs in controlling translation. , 2005, Seminars in cell & developmental biology.

[7]  Martin Reczko,et al.  The database of experimentally supported targets: a functional update of TarBase , 2008, Nucleic Acids Res..

[8]  A. Hatzigeorgiou,et al.  TarBase: A comprehensive database of experimentally supported animal microRNA targets. , 2005, RNA.

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

[10]  M E Greenberg,et al.  The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation , 1995, Molecular and cellular biology.

[11]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[12]  John McClure,et al.  Mapping Affymetrix Microarray Probes to the Rat Genome via a Persistent Index , 2010, Int. J. Knowl. Discov. Bioinform..

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

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

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

[16]  G. Pruijn,et al.  The mammalian exosome mediates the efficient degradation of mRNAs that contain AU‐rich elements , 2002, The EMBO journal.

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

[18]  V. Ambros,et al.  Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity. , 2003, Developmental biology.

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

[20]  Tala Bakheet,et al.  ARED 3.0: the large and diverse AU-rich transcriptome , 2005, Nucleic Acids Res..

[21]  Anton J. Enright,et al.  Requirement of bic/microRNA-155 for Normal Immune Function , 2007, Science.

[22]  N. Perrone-Bizzozero,et al.  Overexpression of HuD, but Not of Its Truncated Form HuD I+II, Promotes GAP‐43 Gene Expression and Neurite Outgrowth in PC12 Cells in the Absence of Nerve Growth Factor , 2000, Journal of neurochemistry.

[23]  Tomasz Imielinski,et al.  Mining association rules between sets of items in large databases , 1993, SIGMOD Conference.

[24]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[25]  Limin Angela Liu.  Interdisciplinary Research and Applications in Bioinformatics, Computational Biology, and Environmental Sciences , 2010 .

[26]  B F Ouellette,et al.  The GenBank sequence database. , 1998, Methods of biochemical analysis.

[27]  Michael Zuker,et al.  Mfold web server for nucleic acid folding and hybridization prediction , 2003, Nucleic Acids Res..

[28]  J. Wilusz,et al.  ELAV proteins stabilize deadenylated intermediates in a novel in vitro mRNA deadenylation/degradation system. , 1999, Genes & development.

[29]  S. Peltz,et al.  The cap-to-tail guide to mRNA turnover , 2001, Nature Reviews Molecular Cell Biology.

[30]  W. Filipowicz,et al.  Regulation of mRNA translation and stability by microRNAs. , 2010, Annual review of biochemistry.

[31]  Doron Betel,et al.  The microRNA.org resource: targets and expression , 2007, Nucleic Acids Res..

[32]  K. McGowan,et al.  Hel-N1, an RNA-binding protein, is a ligand for an A + U rich region of the GLUT1 3' UTR. , 1995, Nucleic acids symposium series.

[33]  M. Karin,et al.  A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery. , 2004, Molecular cell.

[34]  Chris Sander,et al.  Prediction of human microRNA targets. , 2006, Methods in molecular biology.

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

[36]  R. Plasterk,et al.  The diverse functions of microRNAs in animal development and disease. , 2006, Developmental cell.

[37]  S. Cohen,et al.  microRNA functions. , 2007, Annual review of cell and developmental biology.

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

[39]  U. Certa,et al.  Roles of AUF1 isoforms, HuR and BRF1 in ARE-dependent mRNA turnover studied by RNA interference. , 2004, Nucleic acids research.

[40]  S. Hammond,et al.  Emerging paradigms of regulated microRNA processing. , 2010, Genes & development.

[41]  Bing Su,et al.  Small but influential: the role of microRNAs on gene regulatory network and 3'UTR evolution. , 2009, Journal of genetics and genomics = Yi chuan xue bao.

[42]  M. Gorospe,et al.  Influence of the RNA-Binding Protein HuR in pVHL-Regulated p53 Expression in Renal Carcinoma Cells , 2003, Molecular and Cellular Biology.

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

[44]  A. Shyu,et al.  RNA stabilization by the AU‐rich element binding protein, HuR, an ELAV protein , 1998, The EMBO journal.

[45]  Tala Bakheet,et al.  ARED: human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins , 2001, Nucleic Acids Res..

[46]  C. Y. Chen,et al.  Selective degradation of early-response-gene mRNAs: functional analyses of sequence features of the AU-rich elements , 1994, Molecular and cellular biology.

[47]  Tala Bakheet,et al.  ARED 2.0: an update of AU-rich element mRNA database , 2003, Nucleic Acids Res..

[48]  Martti T. Tammi,et al.  MicroTar: predicting microRNA targets from RNA duplexes , 2006, BMC Bioinformatics.

[49]  Matthew He,et al.  Symmetrical Analysis Techniques for Genetic Systems and Bioinformatics: Advanced Patterns and Applications , 2009 .

[50]  M. Levine,et al.  Spatial regulation of microRNA gene expression in the Drosophila embryo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Schneider,et al.  Selective Degradation of AU-Rich mRNAs Promoted by the p37 AUF1 Protein Isoform , 2003, Molecular and Cellular Biology.

[52]  P. Blackshear,et al.  HuR as a negative posttranscriptional modulator in inflammation. , 2005, Molecular cell.

[53]  L. Paillard,et al.  AU-rich elements and associated factors: are there unifying principles? , 2006, Nucleic acids research.

[54]  T. Tomasi,et al.  miRNA regulation of cytokine genes. , 2009, Cytokine.

[55]  Shuang Huang,et al.  Involvement of MicroRNA in AU-Rich Element-Mediated mRNA Instability , 2005, Cell.

[56]  Yixin Chen,et al.  Early Deterioration Warning for Hospitalized Patients by Mining Clinical Data , 2011, Int. J. Knowl. Discov. Bioinform..

[57]  B. Reinhart,et al.  Prediction of Plant MicroRNA Targets , 2002, Cell.

[58]  B. Williams,et al.  AU-rich transient response transcripts in the human genome: expressed sequence tag clustering and gene discovery approach. , 2005, Genomics.

[59]  J. Wilusz,et al.  Bringing the role of mRNA decay in the control of gene expression into focus. , 2004, Trends in genetics : TIG.

[60]  Y. Audic,et al.  Post‐transcriptional regulation in cancer , 2004, Biology of the cell.

[61]  Peter F. Stadler,et al.  Partition function and base pairing probabilities of RNA heterodimers , 2006, Algorithms for Molecular Biology.

[62]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[63]  Dang D. Long,et al.  mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein–enriched transcripts , 2008, Nature Methods.

[64]  P. Blackshear,et al.  Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin , 2007, Expert review of proteomics.

[65]  P. Anderson,et al.  TIA‐1 is a translational silencer that selectively regulates the expression of TNF‐α , 2000 .

[66]  Jennifer Daub,et al.  Expressed sequence tags: medium-throughput protocols. , 2004, Methods in molecular biology.

[67]  Tatiana Tatusova,et al.  NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins , 2004, Nucleic Acids Res..

[68]  Zihua Hu,et al.  MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. , 2008, Molecular immunology.

[69]  I. Karsch-Mizrachi,et al.  The GenBank Sequence , 2002 .

[70]  Anason S. Halees,et al.  ARED Organism: expansion of ARED reveals AU-rich element cluster variations between human and mouse , 2007, Nucleic Acids Res..

[71]  Kevin J Luebke,et al.  Faculty Opinions recommendation of The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. , 2009 .

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

[73]  A. T. Freitas,et al.  Current tools for the identification of miRNA genes and their targets , 2009, Nucleic acids research.

[74]  Nan Li,et al.  MicroRNA-466l Upregulates IL-10 Expression in TLR-Triggered Macrophages by Antagonizing RNA-Binding Protein Tristetraprolin-Mediated IL-10 mRNA Degradation , 2010, The Journal of Immunology.

[75]  A. Shyu,et al.  Versatile Role for hnRNP D Isoforms in the Differential Regulation of Cytoplasmic mRNA Turnover , 2001, Molecular and Cellular Biology.

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

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

[78]  M. Gorospe,et al.  Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs , 2004, The EMBO journal.

[79]  M. Mann,et al.  AU Binding Proteins Recruit the Exosome to Degrade ARE-Containing mRNAs , 2001, Cell.

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

[81]  Oleg Okun.  Feature Selection and Ensemble Methods for Bioinformatics: Algorithmic Classification and Implementations , 2011 .

[82]  N. Perrone-Bizzozero,et al.  The RNA-binding protein HuD is required for GAP-43 mRNA stability, GAP-43 gene expression, and PKC-dependent neurite outgrowth in PC12 cells. , 2000, Molecular biology of the cell.

[83]  Marco Colombi,et al.  Functional cloning of BRF1, a regulator of ARE‐dependent mRNA turnover , 2002, The EMBO journal.

[84]  K. Khabar,et al.  The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. , 2005, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[85]  M. Boguski,et al.  dbEST — database for “expressed sequence tags” , 1993, Nature Genetics.

[86]  Nectarios Koziris,et al.  Accurate microRNA target prediction correlates with protein repression levels , 2009, BMC Bioinformatics.

[87]  Tsung-Cheng Chang,et al.  microRNAs in vertebrate physiology and human disease. , 2007, Annual review of genomics and human genetics.

[88]  J. Steitz,et al.  miRNPs: versatile regulators of gene expression in vertebrate cells. , 2009, Biochemical Society transactions.

[89]  M. Siomi,et al.  Posttranscriptional regulation of microRNA biogenesis in animals. , 2010, Molecular cell.