Summary
MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene silencing mechanism. Intronic miRNAs, derived from introns by RNA splicing and Dicer processing, can interfere with intracellular mRNAs to silence that gene expression. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of type II RNA polymerases (Pol-II) and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in Caenorhabditis elegans, mouse and human cells; however, neither their function nor application has been reported. To this day, the computer searching program for miRNA seldom include the intronic portion of protein-coding RNAs. The functional significance of artificially generated intronic miRNAs has been successfully ascertained in several biological systems such as zebrafishes, chicken embryos and adult mice, indicating the evolutionary preservation of this gene regulation system in vivo. Multiple miRNAs can be generated from the same cluster of introns; however, non-homologous miRNAs may have different targets and functions while homologous miRNA may be derived from different intronic clusters. Taken together, the model of intronic miRNA-mediated transgenic animals provides a tool to investigate the mechanism of miRNA-associated diseases in␣vivo and will shed light on miRNA-related therapies.
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Lin S.L., Chuong C.M., Ying S.Y. (2001) A Novel mRNA-cDNA interference phenomenon for silencing bcl-2 expression in human LNCaP cells. Biochem. Biophys. Res. Commun. 281: 639–644
Lin S.L., Chang D., Wu D.Y., Ying S.Y. (2003) A novel RNA splicing-mediated gene silencing mechanism potential for genome evolution. Biochem Biophys Res Commun. 310: 754–760
Ying S.Y., Lin S.L. (2004) Intron-derived microRNAs–fine tuning of gene functions. Gene 342: 25–28
Clement J.Q., Qian L., Kaplinsky N., Wilkinson M.F. (1999) The stability and fate of a spliced intron from vertebrate cells. RNA 5: 206–220
Ambros V., Lee R.C., Lavanway A., Williams P.T., Jewell D. (2003) MicroRNAs and other tiny endogenous RNAs in C. elegans. Curr Biol. 13: 807–818
Rodriguez A., Griffiths-Jones S., Ashurst J.L., Bradley A. (2004) Identification of mammalian microRNA host genes and transcription units. Genome Res. 14: 1902–1910
Parrish S., Fleenor J., Xu S., Mello C., Fire A. (2000) Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference. Mol. Cell 6: 1077–1087
Holen T., Amarzguioui M., Wiiger M.T., Babaie E., Prydz H. (2002) Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res. 30: 1757–1766
Hutvagner G., Zamore P.D. (2002) A microRNA in a multiple-turnover RNAi enzyme complex. Science 297: 2056–2060
Zeng Y., Yi R., Cullen B.R. (2003) MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc. Natl. Acad. Sci. USA 100: 9779–9784
Hall I.M., Shankaranarayana G.D., Noma K., Ayoub N., Cohen A., Grewal S.I. (2002). Establishment and maintenance of a heterochromatin domain. Science 297: 2232–2237
Llave C., Xie Z., Kasschau K.D., Carrington J.C. (2002). Cleavage of Scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science 297: 2053–2056
Rhoades M.W., Reinhart B.J., Lim L.P., Burge C.B., Bartel B., Bartel D.P. (2002). Prediction of plant microRNA targets. Cell 110: 513–520
Lee R.C., Feibaum R.L., Ambros V. (1993). The C. elegans heterochromic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843–854
Reinhart B.J., Slack F.J., Basson M., Pasquinelli A.E., Bettinger J.C., Rougvie A.E., Horvitz H.R., Ruvkun G. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403: 901–906
Lau N.C., Lim L.P., Weinstein E.G., Bartel D.P. (2001). An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294: 858–862
Brennecke J., Hipfner D.R., Stark A., Russell R.B., Cohen S.M.. (2003). Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113: 25–36
Xu P., Vernooy S.Y., Guo M., Hay B.A. (2003). The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr Biol. 13: 790–795
Lagos-Quintana M., Rauhut R., Meyer J., Borkhardt A., Tuschl T. (2003). New microRNAs from mouse and human. RNA 9: 175–179
Mourelatos Z., Dostie J., Paushkin S., Sharma A., Charroux B., Abel L., Rappsilber J., Mann M., Dreyfuss G. (2002). miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16: 720–728
Zeng Y., Wagner E.J., Cullen B.R. (2002). Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells. Mol Cell 9: 1327–1333
Lin S.L., Chuong C.M., Ying S.Y. (2001). D-RNAi (messenger RNA-antisense DNA interference) as a novel defense system against cancer and viral infections. Curr. Cancer Drug Targets 1: 241–247
Carthew R.W. (2001). Gene silencing by double-stranded RNA. Curr Opin Cell Biol. 13: 244–248
Lee Y., Kim M., Han J., Yeom K.H., Lee S., Baek S.H., Kim V.N. (2004). MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23: 4051–4060
Lee Y., Ahn C., Han J., Choi H., Kim J., Yim J., Lee J., Provost P., Radmark O., Kim S., Kim V.N. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425: 415–419
Lund E., Guttinger S., Calado A., Dahlberg J.E., Kutay U. (2004). Nuclear export of microRNA precursors. Science 303: 95–98
Yi R., Qin Y., Macara I.G., Cullen B.R. (2003). Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 17: 3011–3016
Schwarz D.S., Hutvagner G., Du T., Xu Z., Aronin N., Zamore P.D. (2003). Asymmetry in the assembly of the RNAi enzyme complex. Cell 115: 199–208
Khvorova A., Reynolds A., Jayasena S.D. (2003). Functional siRNAs and miRNAs exhibit strand bias. Cell 115: 209–216
Lee Y.S., Nakahara K., Pham J.W., Kim K., He Z., Sontheimer E.J., Carthew R.W. (2004). Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117: 69–81
Liquori C.L., Ricker K., Moseley M.L., Jacobsen J.F., Kress W., Naylor S.L., Day J.W., Ranum L.P.W. (2001). Myotinic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293: 864–867
Jin P., Alisch R.S., Warren S.T. (2004). RNA and microRNAs in fragile X mental retardation. Nat Cell Biol. 6: 1048–1053
Eberhart D.E., Malter H.E., Feng Y., Warren S.T. (1996). The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum Mol Genet. 5: 1083–1091
Tuschl T., Borkhardt A. (2002). Small interfering RNAs: a revolutionary tool for the analysis of gene function and gene therapy. Mol Interv. 2: 158–167
Miyagishi M., Taira K. (2002). U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol. 20: 497–500
Lee N.S., Dohjima T., Bauer G., Li H., Li M.J., Ehsani A., Salvaterra P., Rossi J. (2002). Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol. 20: 500–505
Paul C.P., Good P.D., Winer I., Engelke D.R. (2002). Effective expression of small interfering RNA in human cells. Nat Biotechnol. 20: 505–508
Xia H., Mao Q., Paulson H.L., Davidson B.L. (2002). siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol. 20: 1006–1010
McCaffrey A.P., Meuse L., Pham T.T., Conklin D.S., Hannon G.J., Kay M.A. (2002). RNA interference in adult mice. Nature 418: 38–39
Gunnery S., Ma Y., Mathews M.B. (1999). Termination sequence requirements vary among genes transcribed by RNA polymerase III. J Mol Biol. 286: 745–757
Schramm L., Hernandez N. (2002). Recruitment of RNA polymerase III to its target promoters. Genes Dev. 16: 2593–2620
Sledz C.A., Holko M., de Veer M.J., Silverman R.H., Williams B.R. (2003). Activation of the interferon system by short-interfering RNAs. Nat Cell Biol. 5: 834–839
Lin S.L., Ying S.Y. (2004). Combinational therapy for HIV-1 eradication and vaccination. Intrn’l J. Oncol. 24: 81–88
Stark G.R., Kerr I.M., Williams B.R, Silverman R.H., Schreiber R.D. (1998). How cells respond to interferons. Annu. Rev. Biochem. 67: 227–264
Lin S.L., Ying S.Y. (2004). New drug design for gene therapy – Taking Advantage of Introns. Lett Drug Design & Discovery 1: 256–262
Lin S.L., Ying S.Y. (2004) Novel RNAi therapy – Intron-derived microRNA drugs. Drug Design Reviews 1: 247–255
Nott A., Meislin S.H., Moore M.J. (2003) A quantitative analysis of intron effects on mammalian gene expression. RNA 9: 607–617
Zhang G., Taneja K.L., Singer R.H., Green M.R. (1994). Localization of pre-mRNA splicing in mammalian nuclei. Nature 372: 809–812
Ghosh S., Garcia-Blanco M.A. (2000). Coupled in vitro synthesis and splicing of RNA polymerase II transcripts. RNA 6: 1325–1334
Ying S.Y., Lin S.L. (2005) Intronic microRNAs. Biochem Biophys Res Commun. 326: 515–520
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This study was supported by NIH/NCI grant CA-85722.
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Ying, SY., Lin, SL. Current perspectives in intronic micro RNAs (miRNAs). J Biomed Sci 13, 5–15 (2006). https://doi.org/10.1007/s11373-005-9036-8
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DOI: https://doi.org/10.1007/s11373-005-9036-8