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  • Review Article
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Insights into RNA structure and function from genome-wide studies

Nature Reviews Genetics volume 15, pages 469–479 (2014)Cite this article

Subjects

Key Points

  • There has been a plethora of experimental approaches that combine traditional chemical probing techniques with next-generation sequencing. These methods have allowed the first glimpse of the 'RNA structurome'.

  • These studies have highlighted, on a genome-wide scale, how RNA structure controls functions and gene expression. It is now possible to identify structural motifs that affect both coding and non-coding RNA function.

  • Each step of protein translation is affected by RNA structure. Generally, the RNA surrounding the start and stops codons is poorly structured to allow ribosome regulation, and the coding region contains structured elements that can regulate protein expression.

  • Small-RNA-binding sites that regulate mRNA expression can be identified through degradome and immunoprecipitation studies to help to predict new small RNAs and their targets.

  • Recent in vivo studies indicate that RNA is less structured, or at least more structurally dynamic, in vivo than in vitro.

  • The future of this research field is likely to explore the structure of low-abundance RNAs, such as long non-coding RNAs, and tertiary RNA structure.

Abstract

A comprehensive understanding of RNA structure will provide fundamental insights into the cellular function of both coding and non-coding RNAs. Although many RNA structures have been analysed by traditional biophysical and biochemical methods, the low-throughput nature of these approaches has prevented investigation of the vast majority of cellular transcripts. Triggered by advances in sequencing technology, genome-wide approaches for probing the transcriptome are beginning to reveal how RNA structure affects each step of protein expression and RNA stability. In this Review, we discuss the emerging relationships between RNA structure and the regulation of gene expression.

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Figure 1: Structural motifs within the transcriptome.
Figure 2: Structure around start codons and translational efficiency.
Figure 3: RNA structure and stability under heat shock.
Figure 4: mRNA structure involved in the regulation of translation by small RNAs.

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References

  1. Sharp, P. A. The centrality of RNA. Cell 136, 577–580 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Cruz, J. A. & Westhof, E. The dynamic landscapes of RNA architecture. Cell 136, 604–609 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Warf, M. B. & Berglund, J. A. Role of RNA structure in regulating pre-mRNA splicing. Trends Biochem. Sci. 35, 169–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. McManus, C. J. & Graveley, B. R. RNA structure and the mechanisms of alternative splicing. Curr. Opin. Genet. Dev. 21, 373–379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kozak, M. Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 361, 13–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Martin, K. C. & Ephrussi, A. mRNA localization: gene expression in the spatial dimension. Cell 136, 719–730 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Garneau, N. L., Wilusz, J. & Wilusz, C. J. The highways and byways of mRNA decay. Nature Rev. Mol. Cell Biol. 8, 113–126 (2007).

    Article  CAS  Google Scholar 

  8. Mauger, D. M., Siegfried, N. A. & Weeks, K. M. The genetic code as expressed through relationships between mRNA structure and protein function. FEBS Lett. 587, 1180–1188 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Merino, E. J., Wilkinson, K. A., Coughlan, J. L. & Weeks, K. M. RNA structure analysis at single nucleotide resolution by selective 2′-hydroxyl acylation and primer extension (SHAPE). J. Am. Chem. Soc. 127, 4223–4231 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Laederach, A., Shcherbakova, I., Jonikas, M. A., Altman, R. B. & Brenowitz, M. Distinct contribution of electrostatics, initial conformational ensemble, and macromolecular stability in RNA folding. Proc. Natl Acad. Sci. 104, 7045–7050 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Adilakshmi, T., Bellur, D. L. & Woodson, S. A. Concurrent nucleation of 16S folding and induced fit in 30S ribosome assembly. Nature 455, 1268–1272 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Weeks, K. M. Advances in RNA structure analysis by chemical probing. Curr. Opin. Struct. Biol. 20, 295–304 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hofacker, I. L. Vienna RNA secondary structure server. Nucleic Acids Res. 31, 3429–3431 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zuker, M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31, 3406–3415 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Disney, M. D., Childs, J. L., Schroeder, S. J., Zuker, M. & Turner, D. H. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proc. Natl Acad. Sci. 101, 7287–7292 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Das, R. et al. Structural inference of native and partially folded RNA by high-throughput contact mapping. Proc. Natl Acad. Sci. 105, 4144–4149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ouyang, Z., Snyder, M. P. & Chang, H. Y. SeqFold: genome-scale reconstruction of RNA secondary structure integrating high-throughput sequencing data. Genome Res. 23, 377–387 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Smith, M. A., Gesell, T., Stadler, P. F. & Mattick, J. S. Widespread purifying selection on RNA structure in mammals. Nucleic Acids Res. 41, 8220–8236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee, J. et al. RNA design rules from a massive open laboratory. Proc. Natl Acad. Sci. 111, 2122–2127 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Kertesz, M. et al. Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103–107 (2010). This paper reports the development of PARS and the secondary structure profile of budding yeast mRNA.

    Article  CAS  PubMed  Google Scholar 

  21. Zheng, Q. et al. Genome-wide double-stranded RNA sequencing reveals the functional significance of base-paired RNAs in Arabidopsis. PLoS Genet. 6, e1001141 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Underwood, J. G. et al. FragSeq: transcriptome-wide RNA structure probing using high-throughput sequencing. 7, 995–1001 (2010). This paper reports the development of FragSeq and uses it to map the structure of the mouse nuclear transcriptome.

  23. Lucks, J. B. et al. Multiplexed RNA structure characterization with selective 2′-hydroxyl acylation analyzed by primer extension sequencing (SHAPE–seq). Proc. Natl Acad. Sci. 108, 11063–11068 (2011). This study presents the first multiplexed approach to structure probing using SHAPE with NGS readout.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li, F. et al. Global analysis of RNA secondary structure in two metazoans. Cell Rep. 1, 69–82 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Li, F. et al. Regulatory impact of RNA secondary structure across the Arabidopsis transcriptome. Plant Cell 24, 4346–4359 (2012). References 24 and 25 apply ds/ssRNA-seq to the A. thaliana, D. melanogaster and C. elegans transcriptomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wan, Y. et al. Genome-wide measurement of RNA folding energies. Mol. Cell 48, 169–181 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Ding, Y. et al. In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505, 696–700 (2013).

    Article  PubMed  CAS  Google Scholar 

  28. Rouskin, S., Zubradt, M., Washietl, S., Kellis, M. & Weissman, J. S. Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo. Nature 505, 701–705 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Wan, Y. et al. Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505, 706–709 (2014). References 27–29 investigate the structure of RNA in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wan, Y., Kertesz, M., Spitale, R. C., Segal, E. & Chang, H. Y. Understanding the transcriptome through RNA structure. Nature Rev. Genet. 12, 641–655 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Silverman, I. M., Li, F. & Gregory, B. D. Genomic era analyses of RNA secondary structure and RNA-binding proteins reveal their significance to post-transcriptional regulation in plants. Plant Science 205–206, 55–62 (2013).

  32. Katz, L. & Burge, C. B. Widespread selection for local RNA secondary structure in coding regions of bacterial genes. Genome Res. 13, 2042–2051 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Watts, J. M. et al. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460, 711–716 (2009). This is the first genome-wide study of RNA structure using SHAPE on ex virio HIV-1 RNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mortimer, S. A. & Weeks, K. M. A fast-acting reagent for accurate analysis of RNA secondary and tertiary structure by SHAPE chemistry. J. Am. Chem. Soc. 129, 4144–4145 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Seetin, M., Kladwang, W., Bida, J. P. & Das, R. Massively parallel RNA chemical mapping with a reduced bias MAP–seq protocol. Methods Mol. Biol. 1086, 95–117 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Shabalina, S. A. A periodic pattern of mRNA secondary structure created by the genetic code. Nucleic Acids Res. 34, 2428–2437 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kudla, G., Murray, A. W., Tollervey, D. & Plotkin, J. B. Coding-sequence determinants of gene expression in Escherichia coli. Science 324, 255–258 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Scharff, L. B., Childs, L., Walther, D. & Bock, R. Local absence of secondary structure permits translation of mRNAs that lack ribosome-binding sites. PLoS Genet. 7, e1002155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gu, W., Zhou, T. & Wilke, C. O. A universal trend of reduced mRNA stability near the translation-initiation site in prokaryotes and eukaryotes. PLoS Comput. Biol. 6, e1000664 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Bentele, K., Saffert, P., Rauscher, R., Ignatova, Z. & Blüthgen, N. Efficient translation initiation dictates codon usage at gene start. Mol. Syst. Biol. 9, 675 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Goodman, D. B., Church, G. M. & Kosuri, S. Causes and effects of N-terminal codon bias in bacterial genes. Science 342, 475–479 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Mao, Y., Wang, W., Cheng, N., Li, Q. & Tao, S. Universally increased mRNA stability downstream of the translation initiation site in eukaryotes and prokaryotes. Gene 517, 230–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Tuller, T., Waldman, Y. Y., Kupiec, M. & Ruppin, E. Translation efficiency is determined by both codon bias and folding energy. Proc. Natl Acad. Sci. 107, 3645–3650 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Komar, A. A. A pause for thought along the co-translational folding pathway. Trends Biochem. Sci. 34, 16–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Wolin, S. L. & Walter, P. Ribosome pausing and stacking during translation of a eukaryotic mRNA. EMBO J. 7, 3559–3569 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shah, P., Ding, Y., Niemczyk, M., Kudla, G. & Plotkin, J. Rate-limiting steps in yeast protein translation. Cell 153, 1589–1601 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Meyer, I. M. Statistical evidence for conserved, local secondary structure in the coding regions of eukaryotic mRNAs and pre-mRNAs. Nucleic Acids Res. 33, 6338–6348 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dana, A. & Tuller, T. Determinants of translation elongation speed and ribosomal profiling biases in mouse embryonic stem cells. PLoS Comput. Biol. 8, e1002755 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nackley, A. G. et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314, 1930–1933 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Wen, J. et al. Following translation by single ribosomes one codon at a time. Nature 452, 598–603 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Han, Y. et al. Monitoring cotranslational protein folding in mammalian cells at codon resolution. Proc. Natl Acad. Sci. 109, 12467–12472 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zur, H. & Tuller, T. Strong association between mRNA folding strength and protein abundance in S. cerevisiae. EMBO Rep. 13, 272–277 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Newman, J. R. S. et al. Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Lee, M. V. et al. A dynamic model of proteome changes reveals new roles for transcript alteration in yeast. Mol. Syst. Biol. 7, 514 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Arava, Y. et al. Genome-wide analysis of mRNA translation profiles in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. 100, 3889–3894 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lécuyer, E. et al. Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function. Cell 131, 174–187 (2007).

    Article  PubMed  CAS  Google Scholar 

  59. Holt, C. E. & Bullock, S. L. Subcellular mRNA localization in animal cells and why it matters. Science 326, 1212–1216 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jambhekar, A. & DeRisi, J. Cis-acting determinants of asymmetric, cytoplasmic RNA transport. RNA 13, 625–642 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chartrand, P., Meng, X. H., Huttelmaier, S., Donato, D. & Singer, R. H. Asymmetric sorting of ash1p in yeast results from inhibition of translation by localization elements in the mRNA. Mol. Cell 10, 1319–1330 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Palazzo, A. F. et al. The signal sequence coding region promotes nuclear export of mRNA. PLoS Biol. 5, e322 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Dienstbier, M., Boehl, F., Li, X. & Bullock, S. L. Egalitarian is a selective RNA-binding protein linking mRNA localization signals to the dynein motor. Genes Dev. 23, 1546–1558 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bullock, S. L., Ringel, I., Ish-Horowicz, D. & Lukavsky, P. J. A′-form RNA helices are required for cytoplasmic mRNA transport in Drosophila. Nature Struct. Mol. Biol. 17, 703–709 (2010).

    Article  CAS  Google Scholar 

  65. Skripkin, E. A., Adhin, M. R., de Smit, M. H. & van Duin, J. Secondary structure of the central region of bacteriophage MS2 RNA. Conservation and biological significance. J. Mol. Biol. 211, 447–463 (1990).

    Article  CAS  PubMed  Google Scholar 

  66. Kortmann, J. & Narberhaus, F. Bacterial RNA thermometers: molecular zippers and switches. Nature Rev. Microbiol. 10, 255–265 (2012).

    Article  CAS  Google Scholar 

  67. Chowdhury, S., Maris, C., Allain, F. H. & Narberhaus, F. Molecular basis for temperature sensing by an RNA thermometer. EMBO J. 25, 2487–2497 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Meyer, M., Plass, M., Pérez-Valle, J., Eyras, E. & Vilardell, J. Deciphering 3′SS selection in the yeast genome reveals an RNA thermosensor that mediates alternative splicing. Mol. Cell 43, 1033–1039 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Vandivier, L. et al. Arabidopsis mRNA secondary structure correlates with protein function and domains. Plant Signal. Behav. 8, e24301 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bonneau, F. et al. The yeast exosome functions as a macromolecular cage to channel RNA substrates for degradation. Cell 139, 547–559 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Panniers, R. Translational control during heat shock. Cell 76, 737–747 (1994).

    CAS  Google Scholar 

  73. Wilson, R. C. & Doudna, J. A. Molecular mechanisms of RNA interference. 42, 217–239 (2013).

  74. Gantier, M. P. & Williams, B. R. G. The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev. 18, 363–371 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U. & Segal, E. The role of site accessibility in microRNA target recognition. Nature Genet. 39, 1278–1284 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Low, J. T. et al. SHAPE-directed discovery of potent shRNA inhibitors of HIV-1. Mol. Ther. 20, 820–828 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ruby, J. G. et al. Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs. Genome Res. 17, 1850–1864 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dai, X., Zhuang, Z. & Zhao, P. X. Computational analysis of miRNA targets in plants: current status and challenges. Brief. Bioinform. 12, 115–121 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Addo-Quaye, C., Eshoo, T. W., Bartel, D. P. & Axtell, M. J. Endogenous siRNA and miRNA targets identified by sequencing of the Arabidopsis degradome. Curr. Biol. 18, 758–762 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. German, M. A. et al. Global identification of microRNA–target RNA pairs by parallel analysis of RNA ends. Nature Biotech. 26, 941–946 (2008).

    Article  CAS  Google Scholar 

  82. Gregory, B. D. et al. A link between RNA metabolism and silencing affecting Arabidopsis development. Dev. Cell 14, 854–866 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Willmann, M. R., Berkowitz, N. D. & Gregory, B. D. Improved genome-wide mapping of uncapped and cleaved transcripts in eukaryotes—GMUCT 2.0. Methods http://dx.doi.org/10.1016/j.ymeth.2013.07.003 (2013).

  84. Chi, S. W., Zang, J. B., Mele, A. & Darnell, R. B. Argonaute HITS–CLIP decodes microRNA–mRNA interaction maps. Nature 479, 479–486 (2009).

    Article  CAS  Google Scholar 

  85. Zisoulis, D. G. et al. Comprehensive discovery of endogenous Argonaute binding sites in Caenorhabditis elegans. Nature Struct. Mol. Biol. 17, 173–179 (2010).

    Article  CAS  Google Scholar 

  86. Yang, J. et al. starBase: a database for exploring microRNA–mRNA interaction maps from Argonaute CLIP–seq and degradome–seq data. Nucleic Acids Res. 39, D202–209 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Li, J., Liu, S., Zhou, H., Qu, L. & Yang, J. starBase v2.0: decoding miRNA–ceRNA, miRNA–ncRNA and protein–RNA interaction networks from large-scale CLIP–seq data. Nucleic Acids Res. 42, D92–D97 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Wells, S. E., Hughes, J. M., Igel, A. H. & Ares, M. Jr. Use of dimethyl sulfate to probe RNA structure in vivo. Methods Enzymol. 318, 479–493 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Ziehler, W. A. & Engelke, D. R. in Current Protocols in Nucleic Acid Chemistry Unit 6.1 (Wiley, 2001).

    Google Scholar 

  90. Spitale, R. C. et al. RNA SHAPE analysis in living cells. Nature Chem. Biol. 9, 18–20 (2012).

    Article  CAS  Google Scholar 

  91. Tyrrell, J., McGinnis, J. L., Weeks, K. M. & Pielak, G. J. The cellular environment stabilizes adenine riboswitch RNA structure. Biochemistry 52, 8777–8785 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Kwok, C. K., Ding, Y., Tang, Y., Assmann, S. M. & Bevilacqua, P. C. Determination of in vivo RNA structure in low-abundance transcripts. Nature Commun. 4, 2971 (2013).

    Article  CAS  Google Scholar 

  93. Tijerina, P., Mohr, S. & Russell, R. DMS footprinting of structured RNAs and RNA–protein complexes. Nature Protoc. 2, 2608–2623 (2007).

    Article  CAS  Google Scholar 

  94. Halvorsen, M., Martin, J. S., Broadaway, S. & Laederach, A. Disease-associated mutations that alter the RNA structural ensemble. PLoS Genet. 6, e1001074 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Stoddard, C. D. et al. Free state conformational sampling of the SAM-I riboswitch aptamer domain. Structure 18, 787–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fang, X. et al. An unusual topological structure of the HIV-1 rev response element. Cell 155, 594–605 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kladwang, W. & Van Lang, C. C., Cordero, P. & Das, R. A two-dimensional mutate-and-map strategy for non-coding RNA structure. Nature Chem. 3, 954–962 (2011).

    Article  CAS  Google Scholar 

  98. Kielpinski, L. J. & Vinther, J. Massive parallel-sequencing-based hydroxyl radical probing of RNA accessibility. Nucleic Acids Res. 42, e70 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mercer, T. R. & Mattick, J. S. Structure and function of long noncoding RNAs in epigenetic regulation. Nature Struct. Mol. Biol. 20, 300–307 (2013).

    Article  CAS  Google Scholar 

  100. Novikova, I. V., Hennelly, S. P., Tung, C. & Sanbonmatsu, K. Y. Rise of the RNA machines: exploring the structure of long non-coding RNAs. J. Mol. Biol. 425, 3731–3746 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Clote, P. Structural RNA has lower folding energy than random RNA of the same dinucleotide frequency. RNA 11, 578–591 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Aviran, S. et al. Modeling and automation of sequencing-based characterization of RNA structure. Proc. Natl Acad. Sci. 108, 11069–11074 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kelly, B. N. et al. Implications for viral capsid assembly from crystal structures of HIV-1 Gag1–278 and CAN133–278 . Biochemistry 45, 11257–11266 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Worthylake, D. K., Wang, H., Yoo, S., Sundquist, W. I. & Hill, C. P. Structures of the HIV-1 capsid protein dimerization domain at 2.6 Å resolution. Acta Crystallogr. D Biol. Crystallogr. 55, 85–92 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to colleagues whose work was not cited owing to space limitation. They thank Y. Bai, R. Wilson, S. Floor, M. Hammond and members of J.A.D.'s laboratory for discussions; K. Weeks for sharing HIV-1 SHAPE data; and J. Ji for reading the manuscript. This work was supported in part by a grant from the US National Institutes of Health (to J.A.D.). J.A.D. is a Howard Hughes Medical Institute Investigator.

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  1. Stefanie A. Mortimer

    Present address: Present address: Guardant Health, Inc., 2686 Middlefield Road, Redwood City, California 94063, USA.,

  2. Stefanie A. Mortimer and Mary Anne Kidwell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley

    Stefanie A. Mortimer, Mary Anne Kidwell & Jennifer A. Doudna

  2. Howard Hughes Medical Institute, University of California, Berkeley

    Jennifer A. Doudna

  3. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    Jennifer A. Doudna

  4. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, 94720, California, USA

    Jennifer A. Doudna

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PowerPoint slides

Glossary

Secondary structures

Two-dimensional non-covalent interactions within an RNA molecule that consist of contiguous base pairs and loops. RNA molecules contain both canonical Watson–Crick base pairs and many non-canonical base pairs.

Tertiary structures

Non-covalent interactions of separate secondary structures within an RNA molecule. These interactions occur between the bases and 2′OH ribose to create precise three- dimensional structures.

Next-generation sequencing

(NGS). A high-throughput technology that simultaneously sequences millions of different DNA molecules by non-Sanger sequencing methods (most commonly sequencing by synthesis).

RNA structurome

The collective group of secondary and tertiary structures formed within the transcriptome of a given organism.

Shine–Dalgarno sequences

Ribosome-binding sites in bacterial mRNA. They are generally located eight bases upstream of the AUG start codon and contain the six-base consensus sequence AGGAGG.

Folding energies

The Gibbs free energies associated with particular RNA folds or structures.

Ribosome profiling

Qualitative and quantitative sequencing of the RNAs attached to ribosomes as a signature of RNAs that are being translated.

Signal peptide

A short peptide of 5–30 amino acids at the amino terminus of newly synthesized proteins in the secretory pathway.

RiboSNitches

Single-nucleotide variants that alter RNA structure and that potentially affect gene regulation.

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Mortimer, S., Kidwell, M. & Doudna, J. Insights into RNA structure and function from genome-wide studies. Nat Rev Genet 15, 469–479 (2014). https://doi.org/10.1038/nrg3681

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