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On the art of identifying effective and specific siRNAs

Abstract

Small interfering RNAs (siRNAs) have been widely exploited for sequence-specific gene knockdown, predominantly to investigate gene function in cultured vertebrate cells, and also hold promise as therapeutic agents. Because not all siRNAs that are cognate to a given target mRNA are equally effective, computational tools have been developed based on experimental data to increase the likelihood of selecting effective siRNAs. Furthermore, because target-complementary siRNAs can also target other mRNAs containing sequence segments that are partially complementary to the siRNA, most computational tools include ways to reduce potential off-target effects in the siRNA selection process. Though these methods facilitate selection of functional siRNAs, they do not yet alleviate the need for experimental validation. This perspective provides a practical guide based on current wisdom for selecting siRNAs.

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Figure 1: A scheme for siRNA-mediated gene silencing.
Figure 2: siRNA and target mRNA structures.

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References

  1. Meister, G. & Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343–349 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Dorsett, Y. & Tuschl, T. siRNAs: applications in functional genomics and potential as therapeutics. Nat. Rev. Drug Discov. 3, 318–329 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Echeverri, C.J. & Perrimon, N. High-throughput RNAi screening in cultured cells: a user's guide. Nat. Rev. Genet. 7, 373–384 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Dykxhoorn, D.M., Palliser, D. & Lieberman, J. The silent treatment: siRNAs as small molecule drugs. Gene Ther. 13, 541–552 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Elbashir, S.M., Harborth, J., Weber, K. & Tuschl, T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 26, 199–213 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Reynolds, A. et al. Rational siRNA design for RNA interference. Nat. Biotechnol. 22, 326–330 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Holen, T., Amarzguioui, M., Wiiger, M.T., Babaie, E. & Prydz, H. Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res. 30, 1757–1766 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Harborth, J. et al. Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev. 13, 83–105 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Birmingham, A. et al. 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat. Methods 3, 199–204 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Jackson, A.L. & Linsley, P.S. Noise amidst the silence: off-target effects of siRNAs? Trends Genet. 20, 521–524 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Lin, X. et al. siRNA-mediated off-target gene silencing triggered by a 7 nt complementation. Nucleic Acids Res. 33, 4527–4535 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jackson, A.L. et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA 12, 1179–1187 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fedorov, Y. et al. Off-target effects by siRNA can induce toxic phenotype. RNA 12, 1188–1196 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huesken, D. et al. Design of a genome-wide siRNA library using an artificial neural network. Nat. Biotechnol. 23, 995–1001 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Saetrom, P. & Snove, O., Jr. A comparison of siRNA efficacy predictors. Biochem. Biophys. Res. Commun. 321, 247–253 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Zhao, H.F. et al. High-throughput screening of effective siRNAs from RNAi libraries delivered via bacterial invasion. Nat. Methods 2, 967–973 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Ito, M., Kawano, K., Miyagishi, M. & Taira, K. Genome-wide application of RNAi to the discovery of potential drug targets. FEBS Lett. 579, 5988–5995 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Kasim, V., Taira, K. & Miyagishi, M. Screening of siRNA target sequences by using fragmentized DNA. J. Gene Med. 8, 782–791 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Sontheimer, E.J. Assembly and function of RNA silencing complexes. Nat. Rev. Mol. Cell Biol. 6, 127–138 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Tomari, Y. & Zamore, P.D. Perspective: machines for RNAi. Genes Dev. 19, 517–529 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Filipowicz, W., Jaskiewicz, L., Kolb, F.A. & Pillai, R.S. Post-transcriptional gene silencing by siRNAs and miRNAs. Curr. Opin. Struct. Biol. 15, 331–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Valencia-Sanchez, M.A., Liu, J., Hannon, G.J. & Parker, R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Hsieh, A.C. et al. A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway: determinants of gene silencing for use in cell-based screens. Nucleic Acids Res. 32, 893–901 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McManus, M.T. et al. Small interfering RNA-mediated gene silencing in T lymphocytes. J. Immunol. 169, 5754–5760 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Ren, Y. et al. siRecords: an extensive database of mammalian siRNAs with efficacy ratings. Bioinformatics 22, 1027–1028 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Chalk, A.M., Warfinge, R.E., Georgii-Hemming, P. & Sonnhammer, E.L. siRNAdb: a database of siRNA sequences. Nucleic Acids Res. 33, D131–D134 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Truss, M. et al. HuSiDa–the human siRNA database: an open-access database for published functional siRNA sequences and technical details of efficient transfer into recipient cells. Nucleic Acids Res. 33, D108–D111 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Smith, C. Sharpening the tools of RNA interference. Nat. Methods 3, 475–486 (2006).

    Article  CAS  Google Scholar 

  29. Shabalina, S.A., Spiridonov, A.N. & Ogurtsov, A.Y. Computational models with thermodynamic and composition features improve siRNA design. BMC Bioinformatics 7, 65 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Yuan, B., Latek, R., Hossbach, M., Tuschl, T. & Lewitter, F. siRNA Selection Server: an automated siRNA oligonucleotide prediction server. Nucleic Acids Res. 32, W130–W134 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chalk, A.M., Wahlestedt, C. & Sonnhammer, E.L. Improved and automated prediction of effective siRNA. Biochem. Biophys. Res. Commun. 319, 264–274 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Ui-Tei, K. et al. Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference. Nucleic Acids Res. 32, 936–948 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Takasaki, S., Kotani, S. & Konagaya, A. An effective method for selecting siRNA target sequences in mammalian cells. Cell Cycle 3, 790–795 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Jagla, B. et al. Sequence characteristics of functional siRNAs. RNA 11, 864–872 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Amarzguioui, M. & Prydz, H. An algorithm for selection of functional siRNA sequences. Biochem. Biophys. Res. Commun. 316, 1050–1058 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Ding, Y., Chan, C.Y. & Lawrence, C.E. Sfold web server for statistical folding and rational design of nucleic acids. Nucleic Acids Res. 32, W135–W141 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Luo, K.Q. & Chang, D.C. The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region. Biochem. Biophys. Res. Commun. 318, 303–310 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Yiu, S.M. et al. Filtering of ineffective siRNAs and improved siRNA design tool. Bioinformatics 21, 144–151 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Kumar, R., Conklin, D.S. & Mittal, V. High-throughput selection of effective RNAi probes for gene silencing. Genome Res. 13, 2333–2340 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Malik, I., Garrido, M., Bahr, M., Kugler, S. & Michel, U. Comparison of test systems for RNAinterference. Biochem. Biophys. Res. Commun. 341, 245–253 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Cullen, B.R. Enhancing and confirming the specificity of RNAi experiments. Nat. Methods 3, 677–681 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Khvorova, A., Reynolds, A. & Jayasena, S.D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Schwarz, D.S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Hutvagner, G. Small RNA asymmetry in RNAi: function in RISC assembly and gene regulation. FEBS Lett. 579, 5850–5857 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Patzel, V. et al. Design of siRNAs producing unstructured guide-RNAs results in improved RNA interference efficiency. Nat. Biotechnol. 23, 1440–1444 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Taxman, D.J. et al. Criteria for effective design, construction, and gene knockdown by shRNA vectors. BMC Biotechnol. 6, 7 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Matranga, C., Tomari, Y., Shin, C., Bartel, D.P. & Zamore, P.D. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123, 607–620 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Manoharan, M. RNA interference and chemically modified small interfering RNAs. Curr. Opin. Chem. Biol. 8, 570–579 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Hossbach, M., Gruber, J., Osborn, M., Weber, K. & Tuschl, T. Gene silencing with siRNA duplexes composed of target-mRNA-complementary and partially palindromic or partially complementary single-stranded siRNAs. RNA Biology 3 (2006).

    Google Scholar 

  50. Cullen, B.R. Induction of stable RNA interference in mammalian cells. Gene Ther. 13, 503–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Heale, B.S., Soifer, H.S., Bowers, C. & Rossi, J.J. siRNA target site secondary structure predictions using local stable substructures. Nucleic Acids Res. 33, e30 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Schubert, S., Grunweller, A., Erdmann, V.A. & Kurreck, J. Local RNA target structure influences siRNA efficacy: systematic analysis of intentionally designed binding regions. J. Mol. Biol. 348, 883–893 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Overhoff, M. et al. Local RNA target structure influences siRNA efficacy: a systematic global analysis. J. Mol. Biol. 348, 871–881 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Mittal, V. Improving the efficiency of RNA interference in mammals. Nat. Rev. Genet. 5, 355–365 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Judge, A.D. et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat. Biotechnol. 23, 457–462 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11, 263–270 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Marques, J.T. & Williams, B.R. Activation of the mammalian immune system by siRNAs. Nat. Biotechnol. 23, 1399–1405 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Judge, A.D., Bola, G., Lee, A.C. & MacLachlan, I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol. Ther. 13, 494–505 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Snøve, O. Jr. & Rossi, J.J. Expressing short hairpin RNAs in vivo. Nat. Methods 3, 689–695 (2006).

    Article  PubMed  CAS  Google Scholar 

  60. Elbashir, S.M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Elbashir, S.M., Lendeckel, W. & Tuschl, T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev. 15, 188–200 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Caplen, N.J., Parrish, S., Imani, F., Fire, A. & Morgan, R.A. Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc. Natl. Acad. Sci. USA 98, 9742–9747 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Paddison, P.J., Caudy, A.A., Bernstein, E., Hannon, G.J. & Conklin, D.S. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 16, 948–958 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kim, D.H. et al. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat. Biotechnol. 23, 222–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Amarzguioui, M., Rossi, J.J. & Kim, D. Approaches for chemically synthesized siRNA and vector-mediated RNAi. FEBS Lett. 579, 5974–5981 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Rose, S.D. et al. Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic Acids Res. 33, 4140–4156 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Reynolds, A. et al. Induction of the interferon response by siRNA is cell type- and duplex length-dependent. RNA 12, 988–993 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Marques, J.T. et al. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat. Biotechnol. 24, 559–565 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Vermeulen, A. et al. The contributions of dsRNA structure to Dicer specificity and efficiency. RNA 11, 674–682 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Jackson, A.L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 21, 635–637 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Haley, B. & Zamore, P.D. Kinetic analysis of the RNAi enzyme complex. Nat. Struct. Mol. Biol. 11, 599–606 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Martinez, J. & Tuschl, T. RISC is a 5′ phosphomonoester-producing RNA endonuclease. Genes Dev. 18, 975–980 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Holen, T. et al. Tolerated wobble mutations in siRNAs decrease specificity, but can enhance activity in vivo. Nucleic Acids Res. 33, 4704–4710 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Elbashir, S.M., Martinez, J., Patkaniowska, A., Lendeckel, W. & Tuschl, T. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J. 20, 6877–6888 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Du, Q., Thonberg, H., Wang, J., Wahlestedt, C. & Liang, Z. A systematic analysis of the silencing effects of an active siRNA at all single-nucleotide mismatched target sites. Nucleic Acids Res. 33, 1671–1677 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dykxhoorn, D.M., Schlehuber, L.D., London, I.M. & Lieberman, J. Determinants of specific RNA interference-mediated silencing of human beta-globin alleles differing by a single nucleotide polymorphism. Proc. Natl. Acad. Sci. USA 103, 5953–5958 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Boese, Q. et al. Mechanistic insights aid computational short interfering RNA design. Methods Enzymol. 392, 73–96 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Santoyo, J., Vaquerizas, J.M. & Dopazo, J. Highly specific and accurate selection of siRNAs for high-throughput functional assays. Bioinformatics 21, 1376–1382 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Naito, Y., Yamada, T., Ui-Tei, K., Morishita, S. & Saigo, K. siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res. 32, W124–W129 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jackson, A.L. et al. Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 12, 1197–1205 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rodriguez-Lebron, E. & Paulson, H.L. Allele-specific RNA interference for neurological disease. Gene Ther. 13, 576–581 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Kubodera, T., Yokota, T., Ishikawa, K. & Mizusawa, H. New RNAi strategy for selective suppression of a mutant allele in polyglutamine disease. Oligonucleotides 15, 298–302 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Samakoglu, S. et al. A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference. Nat. Biotechnol. 24, 89–94 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Martinez, J., Patkaniowska, A., Urlaub, H., Luhrmann, R. & Tuschl, T. Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110, 563–574 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Kittler, R., Heninger, A.K., Franke, K., Habermann, B. & Buchholz, F. Production of endoribonuclease-prepared short interfering RNAs for gene silencing in mammalian cells. Nat. Methods 2, 779–784 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Buchholz, F., Kittler, R., Slabicki, M. & Theis, M. Enzymatically prepared RNAi libraries. Nat. Methods 3, 696–700 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Bernards, R., Brummelkamp, T.R. & Beijersbergen, R.L. shRNA libraries and their use in cancer genetics. Nat. Methods 3, 701–706 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Chang, K., Elledge, S.J. & Hannon, G.J. Lessons from nature: microRNA-based shRNA libraries. Nat. Methods 3, 707–714 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Root, D.E., Hacohen, N., Hahn, W.C., Lander, E.S. & Sabatini, D.M. Genome-scale loss-of-function screening with a lentiviral RNAi library. Nat. Methods 3, 715–719 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Pillai, R.S. MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11, 1753–1761 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yekta, S., Shih, I.H. & Bartel, D.P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Rand, T.A., Petersen, S., Du, F. & Wang, X. Argonaute2 cleaves the anti-guide strand of siRNA during RISC activation. Cell 123, 621–629 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Leuschner, P.J., Ameres, S.L., Kueng, S. & Martinez, J. Cleavage of the siRNA passenger strand during RISC assembly in human cells. EMBO Rep. 7, 314–320 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We apologize to authors whose works are not cited owing to space limitations. We thank C. Echeverri at Cenix Bioscience for valuable discussion. We also thank M. Landthaler, P. Landgraf, J. Brennecke and C. Rogler for critical reading of the manuscript. Y.P. is supported by the Ruth L. Kirschstein Fellowship from the US National Institutes of Health–National Institute of General Medical Sciences.

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Correspondence to Thomas Tuschl.

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T.T. is a cofounder of Alnylam Therapeuticals and serves on its Scientific Advisory Board.

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Pei, Y., Tuschl, T. On the art of identifying effective and specific siRNAs. Nat Methods 3, 670–676 (2006). https://doi.org/10.1038/nmeth911

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