Abstract
An emerging body of evidence indicates that post-transcriptional gene regulation relies not only on the sequence of mRNAs but also on their folding into intricate secondary structures and on the chemical modifications of the RNA bases. These features, which are highly dynamic and interdependent, exert direct control over the transcriptome and thereby influence many aspects of cell function. Here, we consider how the coupling of RNA modifications and structures shapes RNA–protein interactions at different steps of the gene expression process.
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References
Howard, J. M. & Sanford, J. R. The RNAissance family: SR proteins as multifaceted regulators of gene expression. Wiley Interdiscip. Rev. RNA 6, 93–110 (2015).
Huang, Y., Gattoni, R., Stevenin, J. & Steitz, J. A. SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol. Cell 11, 837–843 (2003).
Muller-McNicoll, M. et al. SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export. Genes Dev. 30, 553–566 (2016).
Ji, X. et al. SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153, 855–868 (2013).
Singh, G. et al. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151, 750–764 (2012).
Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129–141 (2010).
Konig, J. et al. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct. Mol. Biol. 17, 909–915 (2010).
Taliaferro, J. M. et al. RNA sequence context effects measured in vitro predict in vivo protein binding and regulation. Mol. Cell 64, 294–306 (2016).
Gilbert, W. V., Bell, T. A. & Schaening, C. Messenger RNA modifications: form, distribution, and function. Science 352, 1408–1412 (2016).
Lu, Z. et al. RNA duplex map in living cells reveals higher-order transcriptome structure. Cell 165, 1267–1279 (2016).
Spitale, R. C. et al. Structural imprints in vivo decode RNA regulatory mechanisms. Nature 519, 486–490 (2015).
Sugimoto, Y. et al. hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature 519, 491–494 (2015).
Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).
Blanc, V. & Davidson, N. O. APOBEC-1-mediated RNA editing. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 594–602 (2010).
Cantara, W. A. et al. The RNA Modification Database, RNAMDB: 2011 update. Nucleic Acids Res. 39, D195–D201 (2011).
El Yacoubi, B., Bailly, M. & de Crecy-Lagard, V. Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu. Rev. Genet. 46, 69–95 (2012).
Karijolich, J., Kantartzis, A. & Yu, Y. T. RNA modifications: a mechanism that modulates gene expression. Methods Mol. Biol. 629, 1–19 (2010).
Barash, Y. et al. Deciphering the splicing code. Nature 465, 53–59 (2010).
Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).
Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).
Schwartz, S. et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 8, 284–296 (2014).
Agarwala, S. D., Blitzblau, H. G., Hochwagen, A. & Fink, G. R. RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet. 8, e1002732 (2012).
Horiuchi, K. et al. Identification of Wilms' tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J. Biol. Chem. 288, 33292–33302 (2013).
Liu, J. et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93–95 (2014).
Patil, D. P. et al. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).
Ping, X. L. et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24, 177–189 (2014).
Zhong, S. et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell 20, 1278–1288 (2008).
Ke, S. et al. A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev. 29, 2037–2053 (2015).
Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011).
Zhao, X. et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 24, 1403–1419 (2014).
Wang, Y. et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 16, 191–198 (2014).
Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).
Zhong, X. Y., Ding, J. H., Adams, J. A., Ghosh, G. & Fu, X. D. Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones. Genes Dev. 23, 482–495 (2009).
Zhong, X. Y., Wang, P., Han, J., Rosenfeld, M. G. & Fu, X. D. SR proteins in vertical integration of gene expression from transcription to RNA processing to translation. Mol. Cell 35, 1–10 (2009).
Xiao, W. et al. Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol. Cell 61, 507–519 (2016).
Haussmann, I.U. et al. m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 540, 301–304 (2016).
Lence, T. et al. m6A modulates neuronal functions and sex determination in Drosophila. Nature 540, 242–247 (2016).
Alarcon, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).
Carlile, T. M. et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143–146 (2014).
Li, X. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat. Chem. Biol. 11, 592–597 (2015).
Lovejoy, A. F., Riordan, D. P. & Brown, P. O. Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae. PLoS ONE 9, e110799 (2014).
Schwartz, S. et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148–162 (2014).
Sommer, S., Lavi, U. & Darnell, J. E. Jr. The absolute frequency of labeled N-6-methyladenosine in HeLa cell messenger RNA decreases with label time. J. Mol. Biol. 124, 487–499 (1978).
Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).
Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).
Du, H. et al. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nat. Commun. 7, 12626 (2016).
Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).
Sheth, U. & Parker, R. Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science 300, 805–808 (2003).
Kennedy, E. M. et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 19, 675–685 (2016).
Chen, T. et al. m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 16, 289–301 (2015).
Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482–485 (2015).
Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).
Mauer, J. et al. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature http://dx.doi.org/10.1038/nature21022 (2016).
Merrick, W. C. Cap-dependent and cap-independent translation in eukaryotic systems. Gene 332, 1–11 (2004).
Wang, X. et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015).
Tirumuru, N. et al. N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife 5 e15528 (2016).
Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015).
Zhou, J. et al. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015).
Feigenblum, D. & Schneider, R. J. Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation. Mol. Cell. Biol. 16, 5450–5457 (1996).
Tang, H. et al. NSun2 delays replicative senescence by repressing p27KIP1 translation and elevating CDK1 translation. Aging (Albany NY) 7, 1143–1158 (2015).
Xing, J. et al. NSun2 promotes cell growth via elevating cyclin-dependent kinase 1 translation. Mol. Cell. Biol. 35, 4043–4052 (2015).
Fu, L. et al. Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J. Am. Chem. Soc. 136, 11582–11585 (2014).
Delatte, B. et al. RNA biochemistry. Transcriptome-wide distribution and function of RNA hydroxymethylcytosine. Science 351, 282–285 (2016).
Dominissini, D. et al. The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA. Nature 530, 441–446 (2016).
Li, X. et al. Transcriptome-wide mapping reveals reversible and dynamic N1-methyladenosine methylome. Nat. Chem. Biol. 12, 311–316 (2016).
Karijolich, J., Yi, C. & Yu, Y. T. Transcriptome-wide dynamics of RNA pseudouridylation. Nat. Rev. Mol. Cell Biol. 16, 581–585 (2015).
Wan, Y., Kertesz, M., Spitale, R. C., Segal, E. & Chang, H. Y. Understanding the transcriptome through RNA structure. Nat. Rev. Genet. 12, 641–655 (2011).
Dethoff, E. A., Chugh, J., Mustoe, A. M. & Al-Hashimi, H. M. Functional complexity and regulation through RNA dynamics. Nature 482, 322–330 (2012).
Cech, T. R. & Steitz, J. A. The noncoding RNA revolution — trashing old rules to forge new ones. Cell 157, 77–94 (2014).
Sharp, P. A. The centrality of RNA. Cell 136, 577–580 (2009).
Smith, D. J., Query, C. C. & Konarska, M. M. “Nought may endure but mutability”: spliceosome dynamics and the regulation of splicing. Mol. Cell 30, 657–666 (2008).
Ding, Y. et al. In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505, 696–700 (2014).
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 (2014).
Liu, S. R., Hu, C. G. & Zhang, J. Z. Regulatory effects of cotranscriptional RNA structure formation and transitions. Wiley Interdiscip. Rev. RNA 7, 562–574 (2016).
Zhang, J. & Landick, R. A. Two-way street: regulatory interplay between RNA polymerase and nascent RNA structure. Trends Biochem. Sci. 41, 293–310 (2016).
Pan, T. & Sosnick, T. RNA folding during transcription. Annu. Rev. Biophys. Biomol. Struct. 35, 161–175 (2006).
de la Mata, M. et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12, 525–532 (2003).
Pinto, P. A. et al. RNA polymerase II kinetics in polo polyadenylation signal selection. EMBO J. 30, 2431–2444 (2011).
Jin, Y., Yang, Y. & Zhang, P. New insights into RNA secondary structure in the alternative splicing of pre-mRNAs. RNA Biol. 8, 450–457 (2011).
Wan, Y. et al. Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505, 706–709 (2014).
Lovci, M. T. et al. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat. Struct. Mol. Biol. 20, 1434–1442 (2013).
Aw, J. G. et al. In vivo mapping of eukaryotic RNA interactomes reveals principles of higher-order organization and regulation. Mol. Cell 62, 603–617 (2016).
Sharma, E., Sterne-Weiler, T., O'Hanlon, D. & Blencowe, B. J. Global mapping of human RNA–RNA interactions. Mol. Cell 62, 618–626 (2016).
Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).
McCloskey, A., Taniguchi, I., Shinmyozu, K. & Ohno, M. hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science 335, 1643–1646 (2012).
Zarnack, K. et al. Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements. Cell 152, 453–466 (2013).
Kertesz, M. et al. Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103–107 (2010).
Wan, Y. et al. Genome-wide measurement of RNA folding energies. Mol. Cell 48, 169–181 (2012).
Bugaut, A. & Balasubramanian, S. 5′-UTR RNA G-quadruplexes: translation regulation and targeting. Nucleic Acids Res. 40, 4727–4741 (2012).
Guo, J. U. & Bartel, D. P. RNA G-quadruplexes are globally unfolded in eukaryotic cells and depleted in bacteria. Science 353 (2016).
Millevoi, S., Moine, H. & Vagner, S. G-Quadruplexes in RNA biology. Wiley Interdiscip. Rev. RNA 3, 495–507 (2012).
Wolfe, A. L. et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70 (2014).
Kenny, P. J. et al. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Rep. 9, 1729–1741 (2014).
Houseley, J., LaCava, J. & Tollervey, D. RNA-quality control by the exosome. Nat. Rev. Mol. Cell Biol. 7, 529–539 (2006).
Geisberg, J. V., Moqtaderi, Z., Fan, X., Ozsolak, F. & Struhl, K. Global analysis of mRNA isoform half-lives reveals stabilizing and destabilizing elements in yeast. Cell 156, 812–824 (2014).
Moqtaderi, Z., Geisberg, J. V. & Struhl, K. Secondary structures involving the poly(A) tail and other 3′ sequences are major determinants of mRNA isoform stability in yeast. Microb. Cell 1, 137–139 (2014).
Spies, N., Burge, C. B. & Bartel, D. P. 3′ UTR-isoform choice has limited influence on the stability and translational efficiency of most mRNAs in mouse fibroblasts. Genome Res. 23, 2078–2090 (2013).
Yang, L., Duff, M. O., Graveley, B. R., Carmichael, G. G. & Chen, L. L. Genomewide characterization of non-polyadenylated RNAs. Genome Biol. 12, R16 (2011).
Marzluff, W. F., Wagner, E. J. & Duronio, R. J. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat. Rev. Genet. 9, 843–854 (2008).
Conrad, N. K., Mili, S., Marshall, E. L., Shu, M. D. & Steitz, J. A. Identification of a rapid mammalian deadenylation-dependent decay pathway and its inhibition by a viral RNA element. Mol. Cell 24, 943–953 (2006).
Conrad, N. K., Shu, M. D., Uyhazi, K. E. & Steitz, J. A. Mutational analysis of a viral RNA element that counteracts rapid RNA decay by interaction with the polyadenylate tail. Proc. Natl Acad. Sci. USA 104, 10412–10417 (2007).
Conrad, N. K. & Steitz, J. A. A. Kaposi's sarcoma virus RNA element that increases the nuclear abundance of intronless transcripts. EMBO J. 24, 1831–1841 (2005).
Brown, J. A., Valenstein, M. L., Yario, T. A., Tycowski, K. T. & Steitz, J. A. Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENβ noncoding RNAs. Proc. Natl Acad. Sci. USA 109, 19202–19207 (2012).
Wilusz, J. E. et al. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 26, 2392–2407 (2012).
Sunwoo, H. et al. MEN ε/β nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 19, 347–359 (2009).
Wilusz, J. E., Freier, S. M. & Spector, D. L. 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135, 919–932 (2008).
Tycowski, K. T., Shu, M. D. & Steitz, J. A. Myriad triple-helix-forming structures in the transposable element RNAs of plants and fungi. Cell Rep. 15, 1266–1276 (2016).
Kierzek, E. & Kierzek, R. The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. Nucleic Acids Res. 31, 4472–4480 (2003).
Roost, C. et al. Structure and thermodynamics of N6-methyladenosine in RNA: a spring-loaded base modification. J. Am. Chem. Soc. 137, 2107–2115 (2015).
Heraud-Farlow, J. E. & Kiebler, M. A. The multifunctional Staufen proteins: conserved roles from neurogenesis to synaptic plasticity. Trends Neurosci. 37, 470–479 (2014).
Csepany, T., Lin, A., Baldick, C. J. Jr & Beemon, K. Sequence specificity of mRNA N6-adenosine methyltransferase. J. Biol. Chem. 265, 20117–20122 (1990).
Horowitz, S., Horowitz, A., Nilsen, T. W., Munns, T. W. & Rottman, F. M. Mapping of N6-methyladenosine residues in bovine prolactin mRNA. Proc. Natl Acad. Sci. USA 81, 5667–5671 (1984).
Liu, N. et al. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA 19, 1848–1856 (2013).
Acknowledgements
A.K. is supported by grants from the US National Institutes of Health (R01HL126845), the March of Dimes (5-FY14-112) and the Center for Advanced Study at the University of Illinois, Chicago, USA. T.P. is supported by the US National Institutes of Health (R01GM113194). The authors apologize to those whose work could not be cited owing to space restraints.
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Lewis, C., Pan, T. & Kalsotra, A. RNA modifications and structures cooperate to guide RNA–protein interactions. Nat Rev Mol Cell Biol 18, 202–210 (2017). https://doi.org/10.1038/nrm.2016.163
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DOI: https://doi.org/10.1038/nrm.2016.163
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