Skip to main content
SpringerLink
Log in

Approaches to the Modulation of miRNA Maturation

  • Protocol
  • First Online:
Book cover miRNA Maturation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1095))

Abstract

The therapeutic importance of microRNA (miRNA) regulation has recently been realized as these small, noncoding RNAs have been demonstrated to be involved with a plethora of diseases and disorders. Due to the complex miRNA maturation process, the expression of these important biomolecules can be manipulated at various stages of the pathway. This review examines both in vivo and in vitro mechanisms and assays that have been developed to regulate miRNA levels. Modulation of miRNA maturation can be accomplished via several therapeutic agents, including small molecules and oligonucleotides, in both specific and nonspecific fashions. Due to the relevance of miRNAs, these novel therapeutic approaches represent new tools for the treatment of various cancers and other deleterious disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hannon GJ (2002) RNA interference. Nature 418(6894):244–251

    Article  PubMed  CAS  Google Scholar 

  2. Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, Baillie DL, Fire A, Ruvkun G, Mello CC (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106(1):23–34

    Article  PubMed  CAS  Google Scholar 

  3. Mattick JS (2001) Non-coding RNAs: the architects of eukaryotic complexity. EMBO Rep 2(11):986–991

    Article  PubMed  CAS  Google Scholar 

  4. Deiters A (2010) Small molecule modifiers of the microRNA and RNA interference pathway. AAPS J 12(1):51–60

    Article  PubMed  CAS  Google Scholar 

  5. Georgianna WE, Young DD (2011) Development and utilization of non-coding RNA-small molecule interactions. Org Biomol Chem 9(23):7969–7978

    Article  PubMed  CAS  Google Scholar 

  6. Mattick JS (2009) Deconstructing the dogma: a new view of the evolution and genetic programming of complex organisms. Ann N Y Acad Sci 1178:29–46

    Article  PubMed  CAS  Google Scholar 

  7. Mattick JS (2010) The central role of RNA in the genetic programming of complex organisms. An Acad Bras Cienc 82(4):933–939

    Article  PubMed  CAS  Google Scholar 

  8. Sun W, Julie Li YS, Huang HD, Shyy JY, Chien S (2010) microRNA: a master regulator of cellular processes for bioengineering systems. Annu Rev Biomed Eng 12:1–27

    Article  PubMed  CAS  Google Scholar 

  9. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233

    Article  PubMed  CAS  Google Scholar 

  10. He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5(7):522–531

    Article  PubMed  CAS  Google Scholar 

  11. Kwak PB, Iwasaki S, Tomari Y (2010) The microRNA pathway and cancer. Cancer Sci 101(11):2309–2315

    Article  PubMed  CAS  Google Scholar 

  12. Ambros V, Chen X (2007) The regulation of genes and genomes by small RNAs. Development 134(9):1635–1641

    Article  PubMed  CAS  Google Scholar 

  13. Garzon R, Marcucci G, Croce CM (2010) Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9(10):775–789

    Article  PubMed  CAS  Google Scholar 

  14. Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 20(16):2202–2207

    Article  PubMed  CAS  Google Scholar 

  15. Czech B, Malone CD, Zhou R, Stark A, Schlingeheyde C, Dus M, Perrimon N, Kellis M, Wohlschlegel JA, Sachidanandam R, Hannon GJ, Brennecke J (2008) An endogenous small interfering RNA pathway in Drosophila. Nature 453(7196):798–802

    Article  PubMed  CAS  Google Scholar 

  16. Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10(2):94–108

    Article  PubMed  CAS  Google Scholar 

  17. Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130(1):89–100

    Article  PubMed  CAS  Google Scholar 

  18. Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, Iwasaki M, Sunamura S, Takeuchi Y, Fukumoto S, Saito K, Nakamura T, Siomi H, Ito H, Arai Y, Shinomiya K, Takeda S (2009) A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A 106(49):20794–20799

    Article  PubMed  CAS  Google Scholar 

  19. Tsai MC, Spitale RC, Chang HY (2011) Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res 71(1):3–7

    Article  PubMed  CAS  Google Scholar 

  20. Weinberg MS, Wood MJ (2009) Short non-coding RNA biology and neurodegenerative disorders: novel disease targets and therapeutics. Hum Mol Genet 18(R1):R27–R39

    Article  PubMed  CAS  Google Scholar 

  21. Kloosterman WP, Plasterk RH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11(4):441–450

    Article  PubMed  CAS  Google Scholar 

  22. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838

    Article  PubMed  CAS  Google Scholar 

  23. Hutvágner G, Simard MJ, Mello CC, Zamore PD (2004) Sequence-specific inhibition of small RNA function. PLoS Biol 2(4):E98

    Article  PubMed  Google Scholar 

  24. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438(7068):685–689

    Article  PubMed  Google Scholar 

  25. Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI, Alder H, Volinia S, Rassenti L, Liu X, Liu CG, Kipps TJ, Negrini M, Croce CM (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A 105(13):5166–5171

    Article  PubMed  CAS  Google Scholar 

  26. Costa FF (2009) Non-coding RNAs and new opportunities for the private sector. Drug Discov Today 14(9–10):446–452

    Article  PubMed  CAS  Google Scholar 

  27. Li Y, He C, Jin P (2010) Emergence of chemical biology approaches to the RNAi/miRNA pathway. Chem Biol 17(6):584–589

    Article  PubMed  CAS  Google Scholar 

  28. Thomas JR, Hergenrother PJ (2008) Targeting RNA with small molecules. Chem Rev 108(4):1171–1224

    Article  PubMed  CAS  Google Scholar 

  29. Zhang S, Chen L, Jung EJ, Calin GA (2010) Targeting microRNAs with small molecules: from dream to reality. Clin Pharmacol Ther 87(6):754–758

    Article  PubMed  CAS  Google Scholar 

  30. Du T, Zamore PD (2005) microPrimer: the biogenesis and function of microRNA. Development 132(21):4645–4652

    Article  PubMed  CAS  Google Scholar 

  31. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956):415–419

    Article  PubMed  CAS  Google Scholar 

  32. Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the Microprocessor complex. Nature 432(7014):231–235

    Article  PubMed  CAS  Google Scholar 

  33. Hutvágner G, McLachlan J, Pasquinelli AE, Bálint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293(5531):834–838

    Article  PubMed  Google Scholar 

  34. Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science 305(5689):1437–1441

    Article  PubMed  CAS  Google Scholar 

  35. Winter J, Jung S, Keller S, Gregory RI, Diederichs S (2009) Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11(3):228–234

    Article  PubMed  CAS  Google Scholar 

  36. Jackson A, Linsley PS (2010) The therapeutic potential of microRNA modulation. Discov Med 9(47):311–318

    PubMed  Google Scholar 

  37. Jackson AL, Linsley PS (2010) Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov 9(1):57–67

    Article  PubMed  CAS  Google Scholar 

  38. Astashkina A, Mann B, Grainger DW (2012) A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther 134(1):82–106

    Article  PubMed  CAS  Google Scholar 

  39. Lipinski C, Hopkins A (2004) Navigating chemical space for biology and medicine. Nature 432(7019):855–861

    Article  PubMed  CAS  Google Scholar 

  40. Gumireddy K, Young D, Xiong X, Hogenesch J, Huang Q, Deiters A (2008) Small-molecule inhibitors of microRNA miR-21 function. Angew Chem Int Ed 47(39):7482–7484

    Article  CAS  Google Scholar 

  41. Young D, Connelly C, Grohmann C, Deiters A (2010) Small molecule modifiers of MicroRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J Am Chem Soc 132(23):7976–7981

    Article  PubMed  CAS  Google Scholar 

  42. Chandrasekhar S, Pushpavalli SN, Chatla S, Mukhopadhyay D, Ganganna B, Vijeender K, Srihari P, Reddy CR, Janaki Ramaiah M, Bhadra U (2012) aza-Flavanones as potent cross-species microRNA inhibitors that arrest cell cycle. Bioorg Med Chem Lett 22(1):645–648

    Article  PubMed  CAS  Google Scholar 

  43. Michlewski G, Guil S, Semple CA, Cáceres JF (2008) Posttranscriptional regulation of miRNAs harboring conserved terminal loops. Mol Cell 32(3):383–393

    Article  PubMed  CAS  Google Scholar 

  44. Guil S, Cáceres JF (2007) The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol 14(7):591–596

    Article  PubMed  CAS  Google Scholar 

  45. Lünse CE, Michlewski G, Hopp CS, Rentmeister A, Cáceres JF, Famulok M, Mayer G (2010) An aptamer targeting the apical-loop domain modulates pri-miRNA processing. Angew Chem Int Ed Engl 49(27):4674–4677

    Article  PubMed  Google Scholar 

  46. Ellington AD (1994) RNA selection. Aptamers achieve the desired recognition. Curr Biol 4(5):427–429

    Article  PubMed  CAS  Google Scholar 

  47. Krishnamurthy M, Simon K, Orendt AM, Beal PA (2007) Macrocyclic helix-threading peptides for targeting RNA. Angew Chem Int Ed Engl 46(37):7044–7047

    Article  PubMed  CAS  Google Scholar 

  48. Lee Y, Hyun S, Kim HJ, Yu J (2008) Amphiphilic helical peptides containing two acridine moieties display picomolar affinity toward HIV-1 RRE and TAR. Angew Chem Int Ed Engl 47(1):134–137

    Article  PubMed  CAS  Google Scholar 

  49. Chirayil S, Chirayil R, Luebke KJ (2009) Discovering ligands for a microRNA precursor with peptoid microarrays. Nucleic Acids Res 37(16):5486–5497

    Article  PubMed  CAS  Google Scholar 

  50. Kwon YU, Kodadek T (2007) Quantitative evaluation of the relative cell permeability of peptoids and peptides. J Am Chem Soc 129(6):1508–1509

    Article  PubMed  CAS  Google Scholar 

  51. Bose D, Jayaraj G, Suryawanshi H, Agarwala P, Pore SK, Banerjee R, Maiti S (2012) The tuberculosis drug streptomycin as a potential cancer therapeutic: inhibition of miR-21 function by directly targeting its precursor. Angew Chem Int Ed Engl 51(4):1019–1023

    Article  PubMed  CAS  Google Scholar 

  52. Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RH (2007) Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biol 5(8):e203

    Article  PubMed  Google Scholar 

  53. Davies BP, Arenz C (2006) A homogenous assay for micro RNA maturation. Angew Chem Int Ed Engl 45(33):5550–5552

    Article  PubMed  CAS  Google Scholar 

  54. Davies BP, Arenz C (2008) A fluorescence probe for assaying micro RNA maturation. Bioorg Med Chem 16(1):49–55

    Article  PubMed  CAS  Google Scholar 

  55. Klemm C, Berthelmann A, Neubacher S, Arenz C (2009) Short and efficient synthesis of alkyne-modified amino glycoside building blocks. Eur J Org Chem 17:2788–2794

    Article  Google Scholar 

  56. Neubacher S, Dojahn CM, Arenz C (2011) A rapid assay for miRNA maturation by using Unmodified pre-miRNA. Chembiochem 12(15):2302–2305

    Article  PubMed  CAS  Google Scholar 

  57. Maiti M, Nauwelaerts K, Herdewijn P (2012) Pre-microRNA binding aminoglycosides and antitumor drugs as inhibitors of Dicer catalyzed microRNA processing. Bioorg Med Chem Lett 22(4):1709–1711

    Article  PubMed  CAS  Google Scholar 

  58. Henn A, Joachimi A, Gonçalves DP, Monchaud D, Teulade-Fichou MP, Sanders JK, Hartig JS (2008) Inhibition of dicing of guanosine-rich shRNAs by quadruplex-binding compounds. Chembiochem 9(16):2722–2729

    Article  PubMed  CAS  Google Scholar 

  59. Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, Faghihi MA, Khalil AM, Lu L, Paroo Z, Chan AW, Shi Z, Liu Q, Wahlestedt C, He C, Jin P (2008) A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol 26(8):933–940

    Article  PubMed  CAS  Google Scholar 

  60. Zhang Q, Zhang C, Xi Z (2008) Enhancement of RNAi by a small molecule antibiotic enoxacin. Cell Res 18(10):1077–1079

    Article  PubMed  CAS  Google Scholar 

  61. Watashi K, Yeung ML, Starost MF, Hosmane RS, Jeang KT (2010) Identification of small molecules that suppress microRNA function and reverse tumorigenesis. J Biol Chem 285(32):24707–24716

    Article  PubMed  CAS  Google Scholar 

  62. Ebert MS, Neilson JR, Sharp PA (2007) MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4(9):721–726

    Article  PubMed  CAS  Google Scholar 

  63. Zheng G, Cochella L, Liu J, Hobert O, Li WH (2011) Temporal and spatial regulation of microRNA activity with photoactivatable cantimirs. ACS Chem Biol 6(12):1332–1338

    Article  PubMed  CAS  Google Scholar 

  64. Achenbach JC, Chiuman W, Cruz RP, Li Y (2004) DNAzymes: from creation in vitro to application in vivo. Curr Pharm Biotechnol 5(4):321–336

    Article  PubMed  CAS  Google Scholar 

  65. Jadhav VM, Scaria V, Maiti S (2009) Antagomirzymes: oligonucleotide enzymes that specifically silence microRNA function. Angew Chem Int Ed Engl 48(14):2557–2560

    Article  PubMed  CAS  Google Scholar 

  66. An CI, Trinh VB, Yokobayashi Y (2006) Artificial control of gene expression in mammalian cells by modulating RNA interference through aptamer-small molecule interaction. RNA 12(5):710–716

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Integrated Science Center, College of William and Mary, Williamsburg, VA, USA

    Valerie T. Tripp, Jaclyn R. McKenna & Douglas D. Young

Authors
  1. Valerie T. Tripp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaclyn R. McKenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas D. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute for Chemistry, Humboldt Universität zu Berlin, Berlin, Berlin, Germany

    Christoph Arenz

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media, New York

About this protocol

Cite this protocol

Tripp, V.T., McKenna, J.R., Young, D.D. (2014). Approaches to the Modulation of miRNA Maturation. In: Arenz, C. (eds) miRNA Maturation. Methods in Molecular Biology, vol 1095. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-703-7_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-703-7_3

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-702-0

  • Online ISBN: 978-1-62703-703-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation