[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Innovation
  • Published:

Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications

Nature Reviews Genetics volume 10, pages 578–585 (2009)Cite this article

Abstract

New technologies are emerging that utilize artificial microRNA (miRNA) target sites to exploit or inhibit endogenous miRNA regulation. This approach has been used to improve cell-specific targeting for gene and stem cell therapy studies and for animal transgenics, and also to reduce the toxicity of oncolytic viruses and to attenuate viral vaccines. Artificial targets have also been used to sponge or decoy miRNAs as a way to study their functions. This article considers the benefits of this approach and design considerations for future studies.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Using microRNA target sites to target transgene and viral expression.
Figure 2: Inhibiting endogenous microRNA function.

Similar content being viewed by others

References

  1. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Griffiths-Jones, S., Saini, H. K., van Dongen, S. & Enright, A. J. miRBase: tools for microRNA genomics. Nucleic Acids Res. 36, D154–D158 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Brown, B. D., Venneri, M. A., Zingale, A., Sergi Sergi, L. & Naldini, L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nature Med. 12, 585–591 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Brown, B. D. et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotechnol. 25, 1457–1467 (2007).

    Article  CAS  Google Scholar 

  6. Barnes, D., Kunitomi, M., Vignuzzi, M., Saksela, K. & Andino, R. Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines. Cell Host Microbe 4, 239–248 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kelly, E. J., Hadac, E. M., Greiner, S. & Russell, S. J. Engineering microRNA responsiveness to decrease virus pathogenicity. Nature Med. 14, 1278–1283 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Papapetrou, E. P., Kovalovsky, D., Beloeil, L., Sant'angelo, D. & Sadelain, M. Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras. J. Clin. Invest. 119, 157–168 (2008).

    PubMed  PubMed Central  Google Scholar 

  9. Edge, R. E. et al. A let-7 microRNA-sensitive vesicular stomatitis virus demonstrates tumor-specific replication. Mol. Ther. 16, 1437–1443 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Suzuki, T. et al. miR-122a-regulated expression of a suicide gene prevents hepatotoxicity without altering antitumor effects in suicide gene therapy. Mol. Ther. 16, 1719–1726 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Ylosmaki, E. et al. Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific microRNA. J. Virol. 82, 11009–11015 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cawood, R. et al. Use of tissue-specific microRNA to control pathology of wild-type adenovirus without attenuation of its ability to kill cancer cells. PLoS Pathog. 5, e1000440 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Mansfield, J. H. et al. MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nature Genet. 36, 1079–1083 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Brown, B. D. et al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 110, 4144–4152 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Care, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613–618 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Ebert, M. S., Neilson, J. R. & Sharp, P. A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nature Methods 4, 721–726 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Scherr, M. et al. Lentivirus-mediated antagomir expression for specific inhibition of miRNA function. Nucleic Acids Res. 35, e149 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bonci, D. et al. The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nature Med. 14, 1271–1277 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Gentner, B. et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nature Methods 6, 63–66 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Kumar, M. S. et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc. Natl. Acad. Sci. USA 105, 3903–3908 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sayed, D. et al. MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol. Biol. Cell 19, 3272–3282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Valastyan, S. et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137, 1032–1046 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kelly, E. J. & Russell, S. J. MicroRNAs and the regulation of vector tropism. Mol. Ther. 17, 409–416 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Waehler, R., Russell, S. J. & Curiel, D. T. Engineering targeted viral vectors for gene therapy. Nature Rev. Genet. 8, 573–587 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Schmidt-Supprian, M. & Rajewsky, K. Vagaries of conditional gene targeting. Nature Immunol. 8, 665–668 (2007).

    Article  CAS  Google Scholar 

  28. De Palma, M. et al. Promoter trapping reveals significant differences in integration site selection between MLV and HIV vectors in primary hematopoietic cells. Blood 105, 2307–2315 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Brown, B. D. & Lillicrap, D. Dangerous liaisons: the role of 'danger' signals in the immune response to gene therapy. Blood 100, 1133–1140 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Cao, O., Furlan-Freguia, C., Arruda, V. R. & Herzog, R. W. Emerging role of regulatory T cells in gene transfer. Curr. Gene Ther. 7, 381–390 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Wolff, L. J., Wolff, J. A. & Sebestyen, M. G. Effect of tissue-specific promoters and microRNA recognition elements on stability of transgene expression after hydrodynamic naked plasmid DNA delivery. Hum. Gene Ther. 20, 374–388 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Neilson, J. R., Zheng, G. X., Burge, C. B. & Sharp, P. A. Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 21, 578–589 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Colin, A. et al. Engineered lentiviral vector targeting astrocytes in vivo. Glia 57, 667–679 (2009).

    Article  PubMed  Google Scholar 

  34. Perez, J. T. et al. MicroRNA-mediated species-specific attenuation of influenza A virus. Nature Biotechnol. 27, 572–576 (2009).

    Article  CAS  Google Scholar 

  35. Haasnoot, J., Westerhout, E. M. & Berkhout, B. RNA interference against viruses: strike and counterstrike. Nature Biotechnol. 25, 1435–1443 (2007).

    Article  CAS  Google Scholar 

  36. Boden, D., Pusch, O., Lee, F., Tucker, L. & Ramratnam, B. Human immunodeficiency virus type 1 escape from RNA interference. J. Virol. 77, 11531–11535 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gitlin, L., Karelsky, S. & Andino, R. Short interfering RNA confers intracellular antiviral immunity in human cells. Nature 418, 430–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Gitlin, L., Stone, J. K. & Andino, R. Poliovirus escape from RNA interference: short interfering RNA–target recognition and implications for therapeutic approaches. J. Virol. 79, 1027–1035 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vignuzzi, M., Wendt, E. & Andino, R. Engineering attenuated virus vaccines by controlling replication fidelity. Nature Med. 14, 154–161 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nature Med. 9, 789–795 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Constien, R. et al. Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis 30, 36–44 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Pucci, F. et al. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes (TEMs), blood 'resident' monocytes and embryonic macrophages suggests common functions and developmental relationships. Blood 21 Apr 2009 (doi:10.1182/blood-2009-01-200931).

    Article  CAS  PubMed  Google Scholar 

  44. Doench, J. G., Petersen, C. P. & Sharp, P. A. siRNAs can function as miRNAs. Genes Dev. 17, 438–442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Haraguchi, T., Ozaki, Y. & Iba, H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 37, e43 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kim, V. N., Han, J. & Siomi, M. C. Biogenesis of small RNAs in animals. Nature Rev. Mol. Cell Biol. 10, 126–139 (2009).

    Article  CAS  Google Scholar 

  47. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).

    Article  PubMed  Google Scholar 

  48. Horwich, M. D. & Zamore, P. D. Design and delivery of antisense oligonucleotides to block microRNA function in cultured Drosophila and human cells. Nature Protoc. 3, 1537–1549 (2008).

    Article  CAS  Google Scholar 

  49. Kloosterman, W. P. & Plasterk, R. H. The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Johnnidis, J. B. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Chen, C. et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33, e179 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Landthaler, M. et al. Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA 14, 2580–2596 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schmitter, D. et al. Effects of Dicer and Argonaute down-regulation on mRNA levels in human HEK293 cells. Nucleic Acids Res. 34, 4801–4815 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xiao, C. et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131, 146–159 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Doench, J. G. & Sharp, P. A. Specificity of microRNA target selection in translational repression. Genes Dev. 18, 504–511 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Seitz, H. Redefining microRNA targets. Curr. Biol. 19, 870–873 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Forstemann, K., Horwich, M. D., Wee, L., Tomari, Y. & Zamore, P. D. Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by dicer-1. Cell 130, 287–297 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Brennecke, J., Stark, A., Russell, R. B. & Cohen, S. M. Principles of microRNA–target recognition. PLoS Biol. 3, e85 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Hutvagner, G. & Zamore, P. D. A microRNA in a multiple-turnover RNAi enzyme complex. Science 297, 2056–2060 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Behm-Ansmant, I. et al. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 20, 1885–1898 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  CAS  PubMed  Google Scholar 

  65. Ameres, S. L., Martinez, J. & Schroeder, R. Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130, 101–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Baccarini, R. Sachidanandam, A. Lombardo, M. De Palma, A. Cantore and B. Gentner for discussions. We apologize to those whose relevant work was not cited here. B.D.B. is supported by the National Institutes for Health (NIH) Diabetes Pathfinder Award (DP2DK083052-01) and L.N. is supported by Fondazione Telethon, the European Union (PERSIST, CONSERT, RIGHT) the NIH, and Associazione Italiana per la Ricerca Sal Cancro.

Author information

Authors and Affiliations

  1. Brian D. Brown is at the Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, BOX 1498, New York, New York 10029, USA. brian.brown@mssm.edu,

    Brian D. Brown

  2. Luigi Naldini is at the San Raffaele Telethon Institute for Gene Therapy and Vita Salute San Raffaele University, San Raffaele Scientific Institute, Via Olgettina, 58, 20132 Milan, Italy. naldini.luigi@hsr.it,

    Luigi Naldini

Authors
  1. Brian D. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luigi Naldini
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Brian D. Brown's homepage

Luigi Naldini's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brown, B., Naldini, L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet 10, 578–585 (2009). https://doi.org/10.1038/nrg2628

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2628

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing