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Analysis of putative miRNA function using a novel approach, GAPPS-miRTarGE

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Abstract

Deciphering the function of miRNA is one of the most important research subjects directed toward understanding the regulation of gene expression. Several experimental methodologies and bioinformatics programs have been developed, however, elucidating miRNA function has not been an easy task. Herein, we suggest a new method, GAPPS-miRTarGE, which is a novel methodology for predicting miRNA function based on the proportion of mRNA targets expressed during embryonic developmental stages, the Theilers stages (TS), in mice. GAPPS-miRTarGE is essentially a computational approach that groups miRNAs using shared expression patterns of their target genes during the 28 different TS. In this study, we present not only several examples derived from the GAPPS-miRTarGE analyses that confirm previously known miRNA functions but also examples of function prediction for valid but functionally unknown miRNAs. Furthermore, we show that tissue-centered GAPPS-miRTarGE, such as brain-centered or heart-centered, is useful for predicting miRNA function on a more detailed level.

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References

  • Agrawal R, Tran U and Wessely O (2009) The miR-30 miRNA family regulates Xenopus pronephros development and targets the transcription factor Xlim1/Lhx1. Development 136: 3927–3936.

    Article  PubMed  CAS  Google Scholar 

  • Baek D, Villen J, Shin C, Camargo FD, Gygi SP and Bartel DP (2008) The impact of microRNAs on protein output. Nature 455: 64–71.

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

    Article  PubMed  CAS  Google Scholar 

  • Betel D, Wilson M, Gabow A, Marks DS and Sander C (2008) The microRNA.org resource: targets and expression. Nucleic Acids Res. 36: D149–D153.

    CAS  Google Scholar 

  • Bhardwaj A, Singh S and Singh AP (2010) MicroRNA-based Cancer Therapeutics: Big Hope from Small RNAs. Mol. Cell. Pharmacol 2: 213–219.

    PubMed  CAS  Google Scholar 

  • Blitzblau RC and Weidhaas JB (2010) MicroRNA binding-site polymorphisms as potential biomarkers of cancer risk. Mol. Diagn. Ther. 14: 335–342.

    PubMed  CAS  Google Scholar 

  • Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, et al. (2009) MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324: 1710–1713.

    Article  PubMed  CAS  Google Scholar 

  • Cho S, Jun Y, Lee S, Choi HS, Jung S, Jang Y, Park C, Kim S and Kim W (2011). miRGator v2.0: an integrated system for functional investigation of microRNAs. Nucleic Acids Res. 39: D158–D162.

    Article  PubMed  Google Scholar 

  • Christensen M and Schratt GM (2009) microRNA involvement in developmental and functional aspects of the nervous system and in neurological diseases. Neurosci. Lett. 466: 55–62.

    Article  PubMed  CAS  Google Scholar 

  • Cordes KR and Srivastava D (2009) MicroRNA regulation of cardiovascular development. Circ. Res. 104: 724–732.

    Article  PubMed  CAS  Google Scholar 

  • Darnell DK, Kaur S, Stanislaw S, Konieczka JH, Yatskievych TA and Antin PB (2006) MicroRNA expression during chick embryo development. Dev. Dyn. 235: 3156–3165.

    Article  PubMed  CAS  Google Scholar 

  • Foshay KM and Gallicano GI (2009) miR-17 family miRNAs are expressed during early mammalian development and regulate stem cell differentiation. Dev. Biol. 326: 431–443.

    Article  PubMed  CAS  Google Scholar 

  • Friedman RC, Farh KK, Burge CB and Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19: 92–105.

    Article  PubMed  CAS  Google Scholar 

  • Ge X, Wu Q and Wang SM (2006) SAGE detects microRNA precursors. BMC Genomics 7: 285.

    Article  PubMed  Google Scholar 

  • Gennarino VA, Sardiello M, Avellino R, Meola N, Maselli V, An, S and Cutillo L, Ballabio A and Banfi S (2009) MicroRNA target prediction by expression analysis of host genes. Genome Res. 19: 481–490.

    Article  PubMed  CAS  Google Scholar 

  • Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, Inoue K, Enright AJ and Schier AF (2006). “Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs.” Science 312: 75–79.

    Article  PubMed  CAS  Google Scholar 

  • Griffiths-Jones S (2006) miRBase: the microRNA sequence database. Methods Mol. Biol. 342: 129–138.

    PubMed  CAS  Google Scholar 

  • Griffiths-Jones S (2010) miRBase: microRNA sequences and annotation. Curr. Protoc. Bioinformatics Chapter 12: Unit 12 9 1–10.

  • Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A and Enright AJ (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 34: D140–D144.

    Article  PubMed  CAS  Google Scholar 

  • Griffiths-Jones S, Saini HK, van Dongen S and Enright AJ (2008) miRBase: tools for microRNA genomics. Nucleic Acids Res. 36: D154–D158.

    Article  PubMed  CAS  Google Scholar 

  • Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP and Bartel DP (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell. 27: 91–105.

    Article  PubMed  CAS  Google Scholar 

  • Hayes B, Fagerlie SR, Ramakrishnan A, Baran S, Harkey M, Graf L, Bar M, Bendoraite A, Tewari M and Torok-Storb B (2008) Derivation, characterization, and in vitro differentiation of canine embryonic stem cells. Stem Cells 26: 465–473.

    Article  PubMed  CAS  Google Scholar 

  • Hebert SS, Horre K, Nicolai L, Bergmans B, Papadopoulou AS, Delacourte A and De Strooper B (2009) MicroRNA regulation of Alzheimer’s Amyloid precursor protein expression. Neurobiol. Dis. 33: 422–428.

    Article  PubMed  CAS  Google Scholar 

  • Herrera BM, Lockstone HE, Taylor JM, Ria M, Barrett A, Collins S, Kaisaki P, Argoud K, Fernandez C, Travers ME, et al. (2010) Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53: 1099–1109.

    Article  PubMed  CAS  Google Scholar 

  • Hicks JA, Tembhurne P and Liu HC (2008) MicroRNA expression in chicken embryos. Poult. Sci. 87: 2335–2343.

    Article  PubMed  CAS  Google Scholar 

  • Hoesel B, Bhujabal Z, Przemeck GK, Kurz-Drexler A, Weisenhorn DM, Angelis MH and Beckers J (2010) Combination of in silico and insitu hybridisation approaches to identify potential Dll1 associated miRNAs during mouse embryogenesis. Gene Expr. Patterns 10: 265–273.

    Article  PubMed  CAS  Google Scholar 

  • Hsu PW, Huang HD, Hsu SD, Lin LZ, Tsou AP, Tseng CP, Stadler PF, Washietl S and Hofacker IL (2006) miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes. Nucleic Acids Res. 34: D135–D139.

    Article  PubMed  CAS  Google Scholar 

  • Hsu SD, Chu CH, Tsou AP, Chen SJ, Chen HC, Hsu PW, Wong YH, Chen YH, Chen GH and Huang HD (2008). miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids Res. 36: D165–D169.

    Article  PubMed  CAS  Google Scholar 

  • Huang B, Li W, Zhao B, Xia C, Liang R, Ruan K, Jing N and Jin Y (2009) MicroRNA expression profiling during neural differentiation of mouse embryonic carcinoma P19 cells. Acta Biochim. Biophys. Sin. (Shanghai) 41: 231–236.

    Article  CAS  Google Scholar 

  • Huang JC, Babak T, Corson TW, Chua G, Khan S, Gallie BL, Hughes TR, Blencowe BJ, Frey BJ and Morris QD (2007) Using expression profiling data to identify human microRNA targets. Nat. Methods 4: 1045–1049.

    Article  PubMed  CAS  Google Scholar 

  • Jiang J, Lee EJ, Gusev Y and Schmittgen TD (2005) Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res. 33: 5394–5403.

    Article  PubMed  CAS  Google Scholar 

  • Kaya KD, Karakulah G, Yakicier CM, Acar AC and Konu O (2011) mESAdb: microRNA expression and sequence analysis database. Nucleic Acids Res. 39: D170–D180.

    Article  PubMed  Google Scholar 

  • Kertesz M, Iovino N, Unnerstall U, Gaul U and Segal E (2007). “The role of site accessibility in microRNA target recognition.” Nat. Genet. 39: 1278–1284.

    Article  PubMed  CAS  Google Scholar 

  • Kozomara A and Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39: D152–D157.

    Article  PubMed  Google Scholar 

  • Kusuda R, Cadetti F, Ravanelli MI, Sousa TA, Zanon S, De Lucca FL and Lucas G (2011) Differential expression of microRNAs in mouse pain models. Mol. Pain 7: 17.

    Article  PubMed  CAS  Google Scholar 

  • Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W and Tuschl T (2002). “Identification of tissue-specific microRNAs from mouse.” Curr. Biol. 12: 735–739.

    Article  PubMed  CAS  Google Scholar 

  • Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M, et al. (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129: 1401–1414.

    Article  PubMed  CAS  Google Scholar 

  • Lau NC, Lim LP, Weinstein EG and Bartel DP (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294: 858–862.

    Article  PubMed  CAS  Google Scholar 

  • Lau P, Verrier JD, Nielsen JA, Johnson KR, Notterpek L and Hudson LD (2008). Identification of dynamically regulated microRNA and mRNA networks in developing oligodendrocytes. J. Neurosci. 28: 11720–11730.

    Article  PubMed  CAS  Google Scholar 

  • Lee CT, Risom T and Strauss WM (2006) MicroRNAs in mammalian development. Birth Defects Res. C Embryo Today 78: 129–139.

    Article  PubMed  CAS  Google Scholar 

  • Lee RC and Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294: 862–864.

    Article  PubMed  CAS  Google Scholar 

  • Lee RC, Feinbaum RL and Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843–854.

    Article  PubMed  CAS  Google Scholar 

  • Lewis BP, Burge CB and Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

    Article  PubMed  CAS  Google Scholar 

  • Li C, Feng Y, Coukos G and Zhang L (2009) Therapeutic microRNA strategies in human cancer. AAPS J. 11: 747–757.

    Article  PubMed  CAS  Google Scholar 

  • Liu CG, Calin GA, Volinia S and Croce CM (2008) MicroRNA expression profiling using microarrays. Nature Protocols 3: 563–578.

    Article  PubMed  CAS  Google Scholar 

  • Makeyev EV, Zhang J, Carrasco MA and Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell. 27: 435–448.

    Article  PubMed  CAS  Google Scholar 

  • Mineno J, Okamoto S, Ando T, Sato M, Chono H, Izu H, Takayama M, Asada K, Mirochnitchenko O, Inouye M and Kato I (2006) The expression profile of microRNAs in mouse embryos. Nucleic Acids Res. 34: 1765–1771.

    Article  PubMed  CAS  Google Scholar 

  • Muhonen P and Holthofer H (2009) Epigenetic and microRNA-mediated regulation in diabetes. Nephrol. Dial. Transplant. 24: 1088–1096.

    Article  PubMed  CAS  Google Scholar 

  • Nam S, Kim B, Shin S and Lee S (2008). miRGator: an integrated system for functional annotation of microRNAs. Nucleic Acids Res. 36: D159–D164.

    Article  PubMed  CAS  Google Scholar 

  • O’Rourke JR, Swanson MS and Harfe BD (2006) MicroRNAs in mammalian development and tumorigenesis. Birth Defects Res. C Embryo Today 78: 172–179.

    Article  PubMed  Google Scholar 

  • Rajewsky N (2006) microRNA target predictions in animals. Nat. Genet. 38Suppl: S8–13.

    Article  PubMed  CAS  Google Scholar 

  • Ransom J and Srivastava D (2007) The genetics of cardiac birth defects. Seminars in Cell & Developmental Biol. 18: 132–139.

    Article  CAS  Google Scholar 

  • Ritchie W, Rajasekhar M, Flamant S and Rasko JE (2009) Conserved expression patterns predict microRNA targets. PLoS Comput. Biol. 5: e1000513.

    Article  PubMed  Google Scholar 

  • Rossi JJ (2009) New hope for a microRNA therapy for liver cancer. Cell 137: 990–992.

    Article  PubMed  CAS  Google Scholar 

  • Ryan BM, Robles AI and Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat. Rev. Cancer 10: 389–402.

    Article  PubMed  CAS  Google Scholar 

  • Sarver AL, Phalak R, Thayanithy V and Subramanian S (2010) S-MED: sarcoma microRNA expression database. Lab. Invest. 90: 753–761.

    Article  PubMed  CAS  Google Scholar 

  • Savolainen SM, Foley JF and Elmore SA (2009). Histology atlas of the developing mouse heart with emphasis on E11.5 to E18.5. Toxicol. Pathol. 37: 395–414.

    Article  PubMed  Google Scholar 

  • Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R and Rajewsky N (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455: 58–63.

    Article  PubMed  CAS  Google Scholar 

  • Sethupathy P, Megraw M and Hatzigeorgiou AG (2006) A guide through present computational approaches for the identification of mammalian microRNA targets. Nature Methods 3: 881–886.

    Article  PubMed  CAS  Google Scholar 

  • Shao P, Zhou H, Xiao ZD, He JH, Huang MB, Chen YQ and Qu LH (2008). Identification of novel chicken microRNAs and analysis of their genomic organization. Gene 418: 34–40.

    Article  PubMed  CAS  Google Scholar 

  • Song L and Tuan RS (2006) MicroRNAs and cell differentiation in mammalian development. Birth Defects Res. C Embryo Today 78: 140–149.

    Article  PubMed  CAS  Google Scholar 

  • Spruce T, Pernaute B, Di-Gregorio A, Cobb BS, Merkenschlager M, Manzanares M and Rodriguez TA (2010) An early developmental role for miRNAs in the maintenance of extraembryonic stem cells in the mouse embryo. Dev. Cell 19: 207–219.

    Article  PubMed  CAS  Google Scholar 

  • Suh MR, Lee Y, Kim JY, Kim SK, Moon SH, Lee JY, Cha KY, Chung HM, Yoon HS, Moon SY, et al. (2004) Human embryonic stem cells express a unique set of microRNAs. Dev. Biol. 270: 488–498.

    Article  PubMed  CAS  Google Scholar 

  • Sweetman D, Rathjen T, Jefferson M, Wheeler G, Smith TG, Wheeler GN, Munsterberg A and Dalmay T (2006). FGF-4 signaling is involved in mir-206 expression in developing somites of chicken embryos. Dev. Dyn. 235: 2185–2191.

    Article  PubMed  CAS  Google Scholar 

  • Theiler K (1989) The house mouse: atlas of embryonic development. Iintelligence 1: 1.

    Google Scholar 

  • Thompson JD, Gibson TJ and Higgins DG (2002) Multiple sequence alignment using ClustalW and ClustalX. Curr. Protoc. Bioinformatics Chapter 2: Unit 2 3.

  • Townley-Tilson WH, Callis TE and Wang D (2009) MicroRNAs 1, 133, and 206: critical factors of skeletal and cardiac muscle development, function, and disease. Int. J. Biochem. Cell Biol. 42: 1252–1255.

    Article  PubMed  Google Scholar 

  • Tsang J, Zhu J and van Oudenaarden A (2007) MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell. 26: 753–767.

    Article  PubMed  CAS  Google Scholar 

  • Tzur G, Israel A, Levy A, Benjamin H, Meiri E, Shufaro Y, Meir K, Khvalevsky E, Spector Y, Rojansky N, et al. (2009) Comprehensive gene and microRNA expression profiling reveals a role for microRNAs in human liver development. PLoS One 4: e7511.

    Article  PubMed  Google Scholar 

  • Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcon M, Oliver PL, Davies KE, Geschwind DH, et al. (2008) A Functional Genetic Link between Distinct Developmental Language Disorders. New Engl. J. Med. 359: 2337–2345.

    Article  PubMed  CAS  Google Scholar 

  • Wang X (2006) Systematic identification of microRNA functions by combining target prediction and expression profiling. Nucleic Acids Res. 34: 1646–1652.

    Article  PubMed  CAS  Google Scholar 

  • Wang X (2008) miRDB: a microRNA target prediction and functional annotation database with a wiki interface. RNA 14: 1012–1017.

    Article  PubMed  CAS  Google Scholar 

  • Wang X (2009) A PCR-based platform for microRNA expression profiling studies. RNA 15: 716–723.

    Article  PubMed  CAS  Google Scholar 

  • Wheeler G, Ntounia-Fousara S, Granda B, Rathjen T and Dalmay T (2006) Identification of new central nervous system specific mouse microRNAs. FEBS Lett. 580: 2195–2200.

    Article  PubMed  CAS  Google Scholar 

  • Wulczyn FG, Smirnova L, Rybak A, Brandt C, Kwidzinski E, Ninnemann O, Strehle M, Seiler A, Schumacher S and Nitsch R (2007) Post-transcriptional regulation of the let-7 microRNA during neural cell specification. FASEB J. 21: 415–426.

    Article  PubMed  CAS  Google Scholar 

  • Zhao Y and Srivastava D (2007) A developmental view of microRNA function. Trends Biochem. Sci. 32: 189–197.

    Article  PubMed  CAS  Google Scholar 

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Park, S.G., Kwon, KH. & Choi, S.S. Analysis of putative miRNA function using a novel approach, GAPPS-miRTarGE . Genes Genom 34, 205–216 (2012). https://doi.org/10.1007/s13258-011-0233-8

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