MicroRNAs (miRNAs) consist of a growing class of non-coding RNAs (ncRNAs) that negatively regulate the expression of genes involved in development, differentiation, proliferation, apoptosis and other important cellular processes. miRNAs are usually 18–25 nt long and are each able to regulate several mRNAs by mechanisms such as incomplete base pairing and Post-Transcriptional Gene Silencing (PTGS). A growing number of reports have shown that aberrant miRNA expression is a common feature of human diseases including cancer, which has sparked interest in targeting these regulators of gene expression as a means of ameliorating these diseases. Here, we review important aspects of miRNA function in normal and pathological states and discuss new modalities of epigenetic intervention strategies that could be used to amend defects in miRNA/mRNA interactions.
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Clinical Epigenetics Open Access 08 May 2010
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Angiotensin II Type 1 receptor
Histone deacetylase 4
Locked nucleic acid anti-sense oligonucleotides
Post-Trancriptional Gene Silencing
RNA Induced Silencing Complex
Serum Response Factor
short hairpin RNAs
small interfering RNAs
Eddy SR . Non-coding RNA genes and the modern RNA world. Nat Rev Genet 2001; 2: 919–929.
Costa FF . Non-coding RNAs: new players in eukaryotic biology. Gene 2005; 357: 83–94.
Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.
Kim VN, Nam JW . Genomics of microRNA. Trends Genet 2006; 22: 165–173.
Wightman B, Ha I, Ruvkun G . Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993; 75: 855–862.
Lee RC, Feinbaum RL, Ambros V . The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843–854.
Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz Jr LA, Sjoblom T et al. The colorectal microRNAome. Proc Natl Acad Sci USA 2006; 103: 3687–3692.
Hsu PW, Huang HD, Hsu SD, Lin LZ, Tsou AP, Tseng CP et al. miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes. Nucleic Acids Res 2006; 34: D135–D139.
Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ . Processing of primary microRNAs by the Microprocessor complex. Nature 2004; 432: 231–235.
Cai X, Hagedorn CH, Cullen BR . Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 2004; 10: 1957–1966.
Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769–773.
Filipowicz W, Jaskiewicz L, Kolb FA, Pillai RS . Post-transcriptional gene silencing by siRNAs and miRNAs. Curr Opin Struct Biol 2005; 15: 331–341.
Hwang HW, Mendell JT . MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer 2006; 94: 776–780.
Esquela-Kerscher A, Slack FJ . Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259–269.
Tang G, Reinhart BJ, Bartel DP, Zamore PD . A biochemical framework for RNA silencing in plants. Genes Dev 2003; 17: 49–63.
Doench JG, Petersen CP, Sharp PA . siRNAs can function as miRNAs. Genes Dev 2003; 17: 438–442.
Zeng Y, Yi R, Cullen BR . MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA 2003; 100: 9779–9784.
Petersen CP, Bordeleau ME, Pelletier J, Sharp PA . Short RNAs repress translation after initiation in mammalian cells. Mol Cell 2006; 21: 533–542.
Rajewsky N . microRNA target predictions in animals. Nat Genet 2006; 38 (Suppl 1): S8–S13.
Lewis BP, Burge CB, Bartel DP . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15–20.
Yi R, O'Carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A et al. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet 2006; 38: 356–362.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M et al. A brain-specific microRNA regulates dendritic spine development. Nature 2006; 439: 283–289.
Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 2006; 38: 228–233.
Naguibneva I, Ameyar-Zazoua M, Polesskaya A, Ait-Si-Ali S, Groisman R, Souidi M et al. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nat Cell Biol 2006; 8: 278–284.
Chen CZ . MicroRNAs as oncogenes and tumor suppressors. N Engl J Med 2005; 353: 1768–1771.
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005; 102: 13944–13949.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A et al. RAS is regulated by the let-7 microRNA family. Cell 2005; 120: 635–647.
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005; 65: 9628–9632.
Chan JA, Krichevsky AM, Kosik KS . MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–6033.
Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 2005; 102: 3627–3632.
Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 2006; 124: 1169–1181.
O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Medell JT . c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435: 839–843.
Martin MM, Lee EJ, Buckenberger JA, Schmittgen TD, Elton TS . Microrna-155 regulates human angiotensin II type 1 receptor expression in fibroblasts. J Biol Chem 2006; 281: 18277–18284.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435: 834–838.
Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353: 1793–1801.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006; 103: 2257–2261.
Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci USA 2006; 103: 7024–7029.
Mirnics K, Pevsner J . Progress in the use of microarray technology to study the neurobiology of disease. Nat Neurosci 2004; 7: 434–439.
Mocellin S, Provenzano M, Rossi CR, Pilati P, Nitti D, Lise M . DNA array-based gene profiling: from surgical specimen to the molecular portrait of cancer. Ann Surg. 2005; 241: 16–26.
Chung CH, Bernard PS, Perou CM . Molecular portraits and the family tree of cancer. Nat Genet. 2002; 32: 533–540.
Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol 2004; 5: R68.
Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS . A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 2003; 9: 1274–1281.
Shingara J, Keiger K, Shelton J, Laosinchai-Wolf W, Powers P, Conrad R et al. An optimized isolation and labeling platform for accurate microRNA expression profiling. RNA 2005; 11: 1461–1470.
Nelson PT, Baldwin DA, Scearce LM, Oberholtzer JC, Tobias JW, Mourelatos Z . Microarray-based, high-throughput gene expression profiling of microRNAs. Nat Methods. 2004; 1: 155–161.
Thomson JM, Parker J, Perou CM, Hammond SM . A custom microarray platform for analysis of microRNA gene expression. Nat Methods 2004; 1: 47–53.
Baskerville S, Bartel DP . Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005; 11: 241–247.
Liang RQ, Li W, Li Y, Tan CY, Li JX, Jin YX et al. An oligonucleotide microarray for microRNA expression analysis based on labeling RNA with quantum dot and nanogold probe. Nucleic Acids Res 2005; 33: e17.
Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich Z et al. MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res 2004; 14: 2486–2494.
Babak T, Zhang W, Morris Q, Blencowe BJ, Hughes TR . Probing microRNAs with microarrays: tissue specificity and functional inference. RNA 2004; 10: 1813–1819.
Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M et al. An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci USA 2004; 101: 9740–9744.
Neely LA, Patel S, Garver J, Gallo M, Hackett M, McLaughlin S et al. A single-molecule method for the quantitation of microRNA gene expression. Nat Methods 2006; 3: 41–46.
Castoldi M, Schmidt S, Benes V, Noerholm M, Kulozik AE, Hentze MW et al. A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA 2006; 12: 913–920.
Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK et al. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 2006; 5: 24.
Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 2005; 33: e179.
Schmittgen TD, Jiang J, Liu Q, Yang L . A high-throughput method to monitor the expression of microRNA precursors. Nucleic Acids Res 2004; 32: e43.
Tang F, Hajkova P, Barton SC, Lao K, Surani MA . MicroRNA expression profiling of single whole embryonic stem cells. Nucleic Acids Res 2006; 34: e9.
Raymond CK, Roberts BS, Garrett-Engele P, Lim LP, Johnson JM . Simple, quantitative primer-extension PCR assay for direct monitoring of microRNAs and short-interfering RNAs. Rna 2005; 11: 1737–1744.
Jiang J, Lee EJ, Gusev Y, Schmittgen TD . Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res 2005; 33: 5394–5403.
Lao K, Xu NL, Yeung V, Chen C, Livak KJ, Straus NA . Multiplexing RT-PCR for the detection of multiple miRNA species in small samples. Biochem Biophys Res Commun 2006; 343: 85–89.
Slack FJ, Weidhaas JB . MicroRNAs as a potential magic bullet in cancer. Future Oncol 2006; 2: 73–82.
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006; 9: 189–198.
Borkhardt A, Fuchs U, Tuschl T . MicroRNA in chronic lymphocytic leukemia. N Engl J Med 2006; 354: 524–525; author reply 524–525.
Ruvkun G . Clarifications on miRNA and cancer. Science 2006; 311: 36–37.
Hammond SM . MicroRNAs as oncogenes. Curr Opin Genet Dev 2006; 16: 4–9.
Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2006; 25: 2537–2545.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 15524–15529.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101: 2999–3004.
Kluiver J, Poppema S, de Jong D, Blokzijl T, Harms G, Jacobs S et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol 2005; 207: 243–249.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al. A microRNA polycistron as a potential human oncogene. Nature 2005; 435: 828–833.
Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64: 3753–3756.
Cao X, Yeo G, Muotri AR, Kuwabara T, Gage FH . Noncoding RNAs in the mammalian central nervous system. Annu Rev Neurosci 2006; 29: 77–103.
Abelson JF, Kwan KY, O'Roak BJ, Baek DY, Stillman AA, Morgan TM et al. Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 2005; 310: 317–320.
Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006; 3: 87–98.
Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV et al. MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 2004; 279: 52361–52365.
Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005; 438: 685–689.
Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004; 432: 226–230.
Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW . Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 2006; 442: 82–85.
Lecellier CH, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, Himber C et al. A cellular microRNA mediates antiviral defense in human cells. Science 2005; 308: 557–560.
Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P . Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005; 309: 1577–1581.
Sullivan CS, Grundhoff AT, Tevethia S, Pipas JM, Ganem D . SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells. Nature 2005; 435: 682–686.
Moffat J, Sabatini DM . Building mammalian signalling pathways with RNAi screens. Nat Rev Mol Cell Biol 2006; 7: 177–187.
Behlke MA . Progress towards in vivo use of siRNAs. Mol Ther 2006; 13: 644–670.
Vidal L, Blagden S, Attard G, de Bono J . Making sense of antisense. Eur J Cancer 2005; 41: 2812–2818.
Jackson AL, Linsley PS . Noise amidst the silence: off-target effects of siRNAs? Trends Genet 2004; 20: 521–524.
Jackson AL, Linsley PS . Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 2003; 21: 635–637.
Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L et al. Widespread siRNA ‘off-target’ transcript silencing mediated by seed region sequence complementarity. RNA 2006; 12: 1179–1187.
Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Federov Y et al. 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods 2006; 3: 199–204.
Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K et al. Off-target effects by siRNA can induce toxic phenotype. RNA 2006; 12: 1188–1196.
Lin X, Ruan X, Anderson MG, McDowell JA, Kroeger PE, Fesik SW et al. siRNA-mediated off-target gene silencing triggered by a 7 nt complementation. Nucleic Acids Res 2005; 33: 4527–4535.
Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006; 441: 537–541.
Mello CC, Conte Jr D . Revealing the world of RNA interference. Nature 2004; 431: 338–342.
Hoheisel JD . Microarray technology: beyond transcript profiling and genotype analysis. Nat Rev Genet 2006; 7: 200–210.
Meister G, Landthaler M, Dorsett Y, Tuschl T . Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 2004; 10: 544–550.
Davis S, Lollo B, Freier S, Esau C . Improved targeting of miRNA with antisense oligonucleotides. Nucleic Acids Res 2006; 34: 2294–2304.
Meister G, Tuschl T . Mechanisms of gene silencing by double-stranded RNA. Nature 2004; 431: 343–349.
Hutvagner G, Simard MJ, Mello CC, Zamore PD . Sequence-specific inhibition of small RNA function. PLoS Biol 2004; 2: E98.
Lee YS, Kim HK, Chung S, Kim KS, Dutta A . Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. J Biol Chem 2005; 280: 16635–16641.
Cheng AM, Byrom MW, Shelton J, Ford LP . Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 2005; 33: 1290–1297.
Baker BF, Lot SS, Condon TP, Cheng-Flournoy S, Lesnik EA, Sasmor HM et al. 2′-O-(2-Methoxy)ethyl-modified anti-intercellular adhesion molecule 1 (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells. J Biol Chem 1997; 272: 11994–12000.
Vester B, Wengel J . LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry 2004; 43: 13233–13241.
Orom UA, Kauppinen S, Lund AH . LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene 2006; 372: 137–141.
Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E et al. MicroRNA expression in zebrafish embryonic development. Science 2005; 309: 310–311.
Kloosterman WP, Wienholds E, de Bruijn E, Kauppinen S, Plasterk RH . In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes. Nat Methods 2006; 3: 27–29.
Chung KH, Hart CC, Al-Bassam S, Avery A, Taylor J, Patel PD et al. Polycistronic RNA polymerase II expression vectors for RNA interference based on BIC/miR-155. Nucleic Acids Res 2006; 34: e53.
Stegmeier F, Hu G, Rickles RJ, Hannon GJ, Elledge SJ . A lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells. Proc Natl Acad Sci USA 2005; 102: 13212–13217.
Brummelkamp TR, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550–553.
Miyagishi M, Taira K . U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol 2002; 20: 497–500.
Xia H, Mao Q, Paulson HL, Davidson BL . siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 2002; 20: 1006–1010.
Plasterk RH . Micro RNAs in animal development. Cell 2006; 124: 877–881.
Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibe B et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 2006.
We thank Dr Xandra O Breakefield, Dr Casey A Maguire, Dr Anna M Krichevsky and Dr Newton V Verbisck for critically reading this manuscript and for helpful suggestions. We also thank Suzanne McDavitt for helping with the manuscript format.
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Wurdinger, T., Costa, F. Molecular therapy in the microRNA era. Pharmacogenomics J 7, 297–304 (2007). https://doi.org/10.1038/sj.tpj.6500429
- non-coding RNAs
- mRNA targets
- multigenic diseases
- ‘epigenetic’ therapy
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