Key Points
-
The alternative splicing regulatory network is modulated by functional coupling between transcription and RNA processing. The transcription machinery can influence alternative splicing decisions by affecting the time in which cis-regulatory elements are transcribed (kinetic model) or by assisting in the recruitment of trans-acting regulatory proteins (recruitment model).
-
Kinetic coupling, which requires changes in the elongation rate of RNA polymerase II (Pol II), can be induced by the presence of transcriptional roadblocks in specific intragenic regions or by modification of the Pol II complex such as phosphorylation of the carboxy-terminal domain (CTD) of its core catalytic subunit.
-
Chromatin structure is a major regulator of splicing, affecting several steps of its coupling with transcription. These include the modulation of transcriptional properties through chromatin conformation and chromatin marks, the recruitment of splicing factors through adaptor proteins that recognize specific histone modifications and specific pausing at exons through preferential nucleosome positioning.
-
Alternative splicing provides multicellular organisms with an extended proteome, the possibility of cell type- and species-specific protein isoforms without increasing the gene number, and the possibility of regulating the production of different proteins through specific signalling pathways. Its importance is supported by the increasing number of diseases associated with alternative splicing misregulation.
-
Emerging evidence indicates that there are common structural and functional features of the polypeptide sequences encoded by alternative cassette exons in comparison to those encoded by constitutive exons. Such features include an increased flexibility and higher number of post-translational modifications.
-
Several gene therapy strategies are being designed to cure hereditary disease by targeting misregulated alternative splicing events. In one of the most advanced studies the use of modified oligonucleotides has proved to be effective in restoring normal levels of a protein defective in spinal muscular atrophy.
Abstract
Alternative splicing was discovered simultaneously with splicing over three decades ago. Since then, an enormous body of evidence has demonstrated the prevalence of alternative splicing in multicellular eukaryotes, its key roles in determining tissue- and species-specific differentiation patterns, the multiple post- and co-transcriptional regulatory mechanisms that control it, and its causal role in hereditary disease and cancer. The emerging evidence places alternative splicing in a central position in the flow of eukaryotic genetic information, between transcription and translation, in that it can respond not only to various signalling pathways that target the splicing machinery but also to transcription factors and chromatin structure.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
20 March 2013
In the above article, the sentence on page 156 should have read: "A minority of budding yeast genes have a single long intron and, interestingly, pausing of Pol II is more abundant in genes that contain short exons than in those containing long exons. This suggests that the presence of a long terminal exon can compensate for faster elongation and help ensure co-transcriptional splicing31." This has been corrected online, and the authors apologize for any confusion caused.
References
Chow, L. T., Gelinas, R. E., Broker, T. R. & Roberts, R. J. An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell 12, 1–8 (1977).
Berget, S. M., Moore, C. & Sharp, P. A. Spliced segments at the 5' terminus of adenovirus 2 late mRNA. Proc. Natl Acad. Sci. USA 74, 3171–3175 (1977).
Pan, Q., Shai, O., Lee, L. J., Frey, B. J. & Blencowe, B. J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genet. 40, 1413–1415 (2008).
Barash, Y. et al. Deciphering the splicing code. Nature 465, 53–59 (2010). Defines a series of features that are characteristic of tissue-specific alternative splicing events and designs an algorithm that is useful to predict tissue-specific changes in alternative splicing patterns.
Nilsen, T. W. & Graveley, B. R. Expansion of the eukaryotic proteome by alternative splicing. Nature 463, 457–463 (2010).
Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nature Rev. Mol. Cell. Biol. 10, 741–754 (2009).
Tejedor, J. R. & Valcárcel, J. Gene regulation: breaking the second genetic code. Nature 465, 45–46 (2010).
Blencowe, B. J. Alternative splicing: new insights from global analyses. Cell 126, 37–47 (2006).
Liang, X. H., Haritan, A., Uliel, S. & Michaeli, S. Trans and cis splicing in trypanosomatids: mechanism, factors, and regulation. Eukaryot. Cell 2, 830–840 (2003).
Howe, K. J., Kane, C. M. & Ares, M. Jr. Perturbation of transcription elongation influences the fidelity of internal exon inclusion in Saccharomyces cerevisiae. RNA 9, 993–1006 (2003).
Salz, H. K. Sex determination in insects: a binary decision based on alternative splicing. Curr. Opin. Genet. Dev. 21, 395–400 (2011).
Park, J. W. & Graveley, B. R. Complex alternative splicing. Adv. Exp. Med. Biol. 623, 50–63 (2007).
Keren, H., Lev-Maor, G. & Ast, G. Alternative splicing and evolution: diversification, exon definition and function. Nature Rev. Genet. 11, 345–355 (2010).
Hynes, R. O. The evolution of metazoan extracellular matrix. J. Cell Biol. 196, 671–679 (2012).
Kafasla, P. et al. Defining the roles and interactions of PTB. Biochem. Soc. Trans. 40, 815–820 (2012).
Jelen, N., Ule, J., Zivin, M. & Darnell, R. B. Evolution of Nova-dependent splicing regulation in the brain. PLoS Genet. 3, 1838–1847 (2007).
Lee, J. A., Tang, Z. Z. & Black, D. L. An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons. Genes Dev. 23, 2284–2293 (2009).
Ule, J. et al. An RNA map predicting Nova-dependent splicing regulation. Nature 444, 580–586 (2006).
Chasin, L. A. Searching for splicing motifs. Adv. Exp. Med. Biol. 623, 85–106 (2007).
Lin, S. & Fu, X. D. SR proteins and related factors in alternative splicing. Adv. Exp. Med. Biol. 623, 107–122 (2007).
Martínez-Contreras, R. et al. hnRNP proteins and splicing control. Adv. Exp. Med. Biol. 623, 123–147 (2007).
Buratti, E. & Baralle, F. E. Influence of RNA secondary structure on the pre-mRNA splicing process. Mol. Cell. Biol. 24, 10505–10514 (2004).
Gelfman, S. et al. Changes in exon–intron structure during vertebrate evolution affect the splicing pattern of exons. Genome Res. 22, 35–50 (2012).
Beyer, A. L. & Osheim, Y. N. Splice site selection, rate of splicing, and alternative splicing on nascent transcripts. Genes Dev. 2, 754–765 (1988).
Khodor, Y. L. et al. Nascent-seq indicates widespread cotranscriptional pre-mRNA splicing in Drosophila. Genes Dev. 25, 2502–2512 (2011).
Listerman, I., Sapra, A. K. & Neugebauer, K. M. Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Nature Struct. Mol. Biol. 13, 815–822 (2006).
Kotovic, K. M., Lockshon, D., Boric, L. & Neugebauer, K. M. Cotranscriptional recruitment of the U1 snRNP to intron-containing genes in yeast. Mol. Cell. Biol. 23, 5768–5779 (2003).
Pandya-Jones, A. & Black, D. L. Co-transcriptional splicing of constitutive and alternative exons. RNA 15, 1896–1908 (2009).
Lacadie, S. A. & Rosbash, M. Cotranscriptional spliceosome assembly dynamics and the role of U1 snRNA:5'ss base pairing in yeast. Mol. Cell 19, 65–75 (2005).
Tilgner, H. et al. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res. 22, 1616–1625 (2012). Provides compelling genome-wide evidence that the vast majority of human introns are excised while still associated with chromatin and reveals that splicing mostly occurs co-transcriptionally.
Carrillo Oesterreich, F., Preibisch, S. & Neugebauer, K. M. Global analysis of nascent RNA reveals transcriptional pausing in terminal exons. Mol. Cell 40, 571–581 (2010).
Ameur, A. et al. Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain. Nature Struct. Mol. Biol. 18, 1435–1440 (2011).
Das, R. et al. SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol. Cell 26, 867–881 (2007).
Vargas, D. Y. et al. Single-molecule imaging of transcriptionally coupled and uncoupled splicing. Cell 147, 1054–1065 (2011).
Bhatt, D. M. et al. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150, 279–290 (2012).
Montes, M., Becerra, S., Sánchez-Álvarez, M. & Suñe, C. Functional coupling of transcription and splicing. Gene 501, 104–117 (2012).
Maniatis, T. & Reed, R. An extensive network of coupling among gene expression machines. Nature 416, 499–506 (2002).
Lazarev, D. & Manley, J. L. Concurrent splicing and transcription are not sufficient to enhance splicing efficiency. RNA 13, 1546–1557 (2007).
Lin, S., Coutinho-Mansfield, G., Wang, D., Pandit, S. & Fu, X. D. The splicing factor SC35 has an active role in transcriptional elongation. Nature Struct. Mol. Biol. 15, 819–826 (2008).
Alexander, R. D., Innocente, S. A., Barrass, J. D. & Beggs, J. D. Splicing-dependent RNA polymerase pausing in yeast. Mol. Cell 40, 582–593 (2010).
Kim, S., Kim, H., Fong, N., Erickson, B. & Bentley, D. L. Pre-mRNA splicing is a determinant of histone H3K36 methylation. Proc. Natl Acad. Sci. USA 108, 13564–13569 (2011).
de Almeida, S. F. et al. Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nature Struct. Mol. Biol. 18, 977–983 (2011).
Brody, Y. et al. The in vivo kinetics of RNA polymerase II elongation during co-transcriptional splicing. PLoS Biol. 9, e1000573 (2011).
Eperon, L. P., Graham, I. R., Griffiths, A. D. & Eperon, I. C. Effects of RNA secondary structure on alternative splicing of pre-mRNA: is folding limited to a region behind the transcribing RNA polymerase? Cell 54, 393–401 (1988).
Cramer, P. et al. Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer. Mol. Cell 4, 251–258 (1999).
Cramer, P., Pesce, C. G., Baralle, F. E. & Kornblihtt, A. R. Functional association between promoter structure and transcript alternative splicing. Proc. Natl Acad. Sci. USA 94, 11456–11460 (1997). First evidence that alternative splicing is coupled to transcription.
Pagani, F., Stuani, C., Zuccato, E., Kornblihtt, A. R. & Baralle, F. E. Promoter architecture modulates CFTR exon 9 skipping. J. Biol. Chem. 278, 1511–1517 (2003).
Kadener, S. et al. Antagonistic effects of T-Ag and VP16 reveal a role for RNA Pol II elongation on alternative splicing. EMBO J. 20, 5759–5768 (2001).
Nogués, G., Kadener, S., Cramer, P., Bentley, D. & Kornblihtt, A. R. Transcriptional activators differ in their abilities to control alternative splicing. J. Biol. Chem. 277, 43110–43114 (2002).
Auboeuf, D. et al. Differential recruitment of nuclear receptor coactivators may determine alternative RNA splice site choice in target genes. Proc. Natl Acad. Sci. USA 101, 2270–2274 (2004).
Auboeuf, D. et al. CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing. Mol. Cell. Biol. 24, 442–453 (2004).
Auboeuf, D., Honig, A., Berget, S. M. & O'Malley, B. W. Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298, 416–419 (2002).
Kadener, S., Fededa, J. P., Rosbash, M. & Kornblihtt, A. R. Regulation of alternative splicing by a transcriptional enhancer through RNA Pol II elongation. Proc. Natl Acad. Sci. USA 99, 8185–8190 (2002).
Kornblihtt, A. R., de la Mata, M., Fededa, J. P., Muñoz, M. J. & Nogués, G. Multiple links between transcription and splicing. RNA 10, 1489–1498 (2004).
Batsché, E., Yaniv, M. & Muchardt, C. The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nature Struct. Mol. Biol. 13, 22–29 (2006). First demonstration that a chromatin remodelling factor regulates alternative splicing through intragenic control of transcriptional elongation.
Alló, M. et al. Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nature Struct. Mol. Biol. 16, 717–724 (2009). First demonstration that small non-coding RNAs can regulate alternative splicing through a nuclear silencing mechanism that alters chromatin and inhibits transcriptional elongation.
Schor, I. E., Rascovan, N., Pelisch, F., Alló, M. & Kornblihtt, A. R. Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc. Natl Acad. Sci. USA 106, 4325–4330 (2009).
Saint-André, V., Batsché, E., Rachez, C. & Muchardt, C. Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative exons. Nature Struct. Mol. Biol. 18, 337–344 (2011).
Luco, R. F. et al. Regulation of alternative splicing by histone modifications. Science 327, 996–1000 (2010). Demonstrates that intragenic histone post-translational modifications can regulate alternative splicing through the indirect recruitment of specific splicing factors.
Pradeepa, M. M., Sutherland, H. G., Ule, J., Grimes, G. R. & Bickmore, W. A. Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS Genet. 8, e1002717 (2012).
Muñoz, M. J., de la Mata, M. & Kornblihtt, A. R. The carboxy terminal domain of RNA polymerase II and alternative splicing. Trends Biochem. Sci. 35, 497–504 (2010).
de la Mata, M. & Kornblihtt, A. R. RNA polymerase II C-terminal domain mediates regulation of alternative splicing by SRp20. Nature Struct. Mol. Biol. 13, 973–980 (2006).
Monsalve, M. et al. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol. Cell 6, 307–316 (2000).
Huang, Y. et al. Mediator complex regulates alternative mRNA processing via the MED23 subunit. Mol. Cell 45, 459–469 (2012). Shows that a fundamental complex of the eukaryotic transcription regulatory machinery, the Mediator complex, has a pivotal role in the control of alternative splicing.
Roberts, G. C., Gooding, C., Mak, H. Y., Proudfoot, N. J. & Smith, C. W. Co-transcriptional commitment to alternative splice site selection. Nucleic Acids Res. 26, 5568–5572 (1998).
Nogués, G., Muñoz, M. J. & Kornblihtt, A. R. Influence of polymerase II processivity on alternative splicing depends on splice site strength. J. Biol. Chem. 278, 52166–52171 (2003).
Ip, J. Y. et al. Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Res. 21, 390–401 (2011). Shows that inhibiting Pol II-mediated elongation through different means has similar global effects on alternative splicing and demonstrates the generality of elongation control.
Shukla, S. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479, 74–79 (2011). Demonstrates that the chromatin-insulating factor CTCF also acts in an intragenic manner by binding to unmethylated CpG islands and by creating roadblocks to Pol II-mediated elongation that affect alternative splicing decisions.
Oberdoerffer, S. A conserved role for intragenic DNA methylation in alternative pre-mRNA splicing. Transcription 3, 106–109 (2012).
Close, P. et al. DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation. Nature 484, 386–389 (2012).
Chen, Y., Chafin, D., Price, D. H. & Greenleaf, A. L. Drosophila RNA polymerase II mutants that affect transcription elongation. J. Biol. Chem. 271, 5993–5999 (1996).
Boireau, S. et al. The transcriptional cycle of HIV-1 in real-time and live cells. J. Cell. Biol. 179, 291–304 (2007).
de la Mata, M. et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12, 525–532 (2003). Direct evidence, using a slow Pol II mutant, that transcriptional elongation affects alternative splicing decisions.
Montes, M. et al. TCERG1 regulates alternative splicing of the Bcl-x gene by modulating the rate of RNA polymerase II transcription. Mol. Cell. Biol. 32, 751–762 (2012).
Aebi, M. & Weissmann, C. Precision and orderliness in splicing. Trends Genet. 3, 102–107 (1987).
de la Mata, M., Lafaille, C. & Kornblihtt, A. R. First come, first served revisited: factors affecting the same alternative splicing event have different effects on the relative rates of intron removal. RNA 16, 904–912 (2010).
Dutertre, M. et al. Cotranscriptional exon skipping in the genotoxic stress response. Nature Struct. Mol. Biol. 17, 1358–1366 (2010).
Solier, S. et al. Genome-wide analysis of novel splice variants induced by topoisomerase I poisoning shows preferential occurrence in genes encoding splicing factors. Cancer Res. 70, 8055–8065 (2010).
Dujardin, G. et al. CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3. Nucleic Acids Res. 38, 7273–7285 (2010).
Schmidt, U. et al. Real-time imaging of cotranscriptional splicing reveals a kinetic model that reduces noise: implications for alternative splicing regulation. J. Cell Biol. 193, 819–829 (2011).
Darzacq, X. et al. In vivo dynamics of RNA polymerase II transcription. Nature Struct. Mol. Biol. 14, 796–806 (2007).
Muñoz, M. J. et al. DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation. Cell 137, 708–720 (2009). Demonstration that UV light-mediated DNA damage promotes Pol II hyperphosphorylation, resulting in decreased transcriptional elongation rates that affect many alternative splicing events.
Alló, M. et al. Chromatin and alternative splicing. Cold Spring Harb. Symp. Quant. Biol. 75, 103–111 (2010).
Luco, R. F., Alló, M., Schor, I. E., Kornblihtt, A. R. & Misteli, T. Epigenetics in alternative pre-mRNA splicing. Cell 144, 16–26 (2011).
Waldholm, J. et al. SWI/SNF regulates the alternative processing of a specific subset of pre-mRNAs in Drosophila melanogaster. BMC Mol. Biol. 12, 46 (2011).
Kolasinska-Zwierz, P. et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nature Genet. 41, 376–381 (2009).
Ameyar-Zazoua, M. et al. Argonaute proteins couple chromatin silencing to alternative splicing. Nature Struct. Mol. Biol. 19, 998–1004 (2012).
Andersson, R., Enroth, S., Rada-Iglesias, A., Wadelius, C. & Komorowski, J. Nucleosomes are well positioned in exons and carry characteristic histone modifications. Genome Res. 19, 1732–1741 (2009).
Schwartz, S., Meshorer, E. & Ast, G. Chromatin organization marks exon–intron structure. Nature Struct. Mol. Biol. 16, 990–995 (2009).
Spies, N., Nielsen, C. B., Padgett, R. A. & Burge, C. B. Biased chromatin signatures around polyadenylation sites and exons. Mol. Cell 36, 245–254 (2009).
Tilgner, H. et al. Nucleosome positioning as a determinant of exon recognition. Nature Struct. Mol. Biol. 16, 996–1001 (2009). References 89, 90 and 91 provide genome-wide evidence that nucleosomes are preferentially positioned on exons, further supporting the idea of coupling between chromatin, transcription, splicing and alternative splicing.
Berget, S. M. Exon recognition in vertebrate splicing. J. Biol. Chem. 270, 2411–2414 (1995).
Hodges, C., Bintu, L., Lubkowska, L., Kashlev, M. & Bustamante, C. Nucleosomal fluctuations govern the transcription dynamics of RNA polymerase II. Science 325, 626–628 (2009).
Churchman, L. S. & Weissman, J. S. Nascent transcript sequencing visualizes transcription at nucleotide resolution. Nature 469, 368–373 (2011).
Ellis, J. D. et al. Tissue-specific alternative splicing remodels protein–protein interaction networks. Mol. Cell 46, 884–892 (2012).
Buljan, M. et al. Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Mol. Cell 46, 871–883 (2012). Provides evidence for common structural and functional features of the polypeptide sequences encoded by alternative cassette exons that are different from those of sequences encoded by constitutive exons.
Gabut, M. et al. An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming. Cell 147, 132–146 (2011).
Taliaferro, J. M., Álvarez, N., Green, R. E., Blanchette, M. & Rio, D. C. Evolution of a tissue-specific splicing network. Genes Dev. 25, 608–620 (2011).
Pan, Q. et al. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol. Cell 16, 929–941 (2004).
Gracheva, E. O. et al. Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature 476, 88–91 (2011). Provides an excellent example of the biological importance of alternative splicing. Demonstrates that vampire bats use a cell type- and species-specific splicing variant of a neuron ion channel to sense infrared radiation in order to spot their prey.
Calarco, J. A. et al. Global analysis of alternative splicing differences between humans and chimpanzees. Genes Dev. 21, 2963–2975 (2007).
Barbosa-Morais, N. L. et al. The evolutionary landscape of alternative splicing in vertebrate species. Science 338, 1587–1593 (2012).
Heyd, F. & Lynch, K. W. Degrade, move, regroup: signaling control of splicing proteins. Trends Biochem. Sci. 36, 397–404 (2011).
Lynch, K. W. Regulation of alternative splicing by signal transduction pathways. Adv. Exp. Med. Biol. 623, 161–174 (2007).
Blaustein, M., Pelisch, F. & Srebrow, A. Signals, pathways and splicing regulation. Int. J. Biochem. Cell Biol. 39, 2031–2048 (2007).
Matter, N., Herrlich, P. & Konig, H. Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 420, 691–695 (2002).
Heyd, F. & Lynch, K. W. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol. Cell 40, 126–137 (2010).
Blaustein, M. et al. Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT. Nature Struct. Mol. Biol. 12, 1037–1044 (2005).
Zhou, Z. et al. The Akt–SRPK–SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol. Cell 47, 422–433 (2012). Elucidates the signalling cascade through which EGF can control alternative splicing.
Amin, E. M. et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 20, 768–780 (2011).
van der Houven van Oordt, W. et al. The MKK3/6–p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J. Cell Biol. 149, 307–316 (2000).
Shomron, N., Alberstein, M., Reznik, M. & Ast, G. Stress alters the subcellular distribution of hSlu7 and thus modulates alternative splicing. J. Cell Sci. 118, 1151–1159 (2005).
Daoud, R. et al. Ischemia induces a translocation of the splicing factor tra2-β1 and changes alternative splicing patterns in the brain. J. Neurosci. 22, 5889–5899 (2002).
Schor, I. E. et al. Perturbation of chromatin structure globally affects localization and recruitment of splicing factors. PLoS ONE. 7, e48084 (2012).
Orengo, J. P. & Cooper, T. A. Alternative splicing in disease. Adv. Exp. Med. Biol. 623, 212–223 (2007).
Srebrow, A. & Kornblihtt, A. R. The connection between splicing and cancer. J. Cell Sci. 119, 2635–2641 (2006).
Venables, J. P. et al. Cancer-associated regulation of alternative splicing. Nature Struct. Mol. Biol. 16, 670–676 (2009).
David, C. J. & Manley, J. L. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 24, 2343–2364 (2010).
Baralle, D., Lucassen, A. & Buratti, E. Missed threads. The impact of pre-mRNA splicing defects on clinical practice. EMBO Rep. 10, 810–816 (2009).
Pagani, F. & Baralle, F. E. Genomic variants in exons and introns: identifying the splicing spoilers. Nature Rev. Genet. 5, 389–396 (2004).
Gabellini, D. et al. Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature 439, 973–977 (2006).
Anczukow, O. et al. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nature Struct. Mol. Biol. 19, 220–228 (2012).
Ghigna, C. et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol. Cell 20, 881–890 (2005).
David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 463, 364–368 (2010).
Tarn, W. Y. & Steitz, J. A. A novel spliceosome containing U11, U12, and U5 snRNPs excises a minor class (AT–AC) intron in vitro. Cell 84, 801–811 (1996).
Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).
Fernández Alanis, E. et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum. Mol. Genet. 21, 2389–2398 (2012).
Liu, X. et al. Partial correction of endogenous ΔF508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing. Nature Biotechnol. 20, 47–52 (2002).
Hua, Y. & Krainer, A. R. Antisense-mediated exon inclusion. Methods Mol. Biol. 867, 307–323 (2012).
Hua, Y. et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24, 1634–1644 (2010).
Hua, Y. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123–126 (2011). Powerful procedure that uses sequence-specific oligonucleotides to cure SMA in a mouse model by regulating alternative splicing of Smn (survival motor neuron).
McGuire, A., Pearson, M., Neafsey, D. & Galagan, J. Cross-kingdom patterns of alternative splicing and splice recognition. Genome Biol. 9, R50 (2008).
Reddy, A. Alternative splicing of pre-messenger RNAs in plants in the genomic era. Annu. Rev. Plant Biol. 58, 267–361 (2007).
Márquez, Y., Brown, J., Simpson, C., Barta, A. & Kalyna, M. Transcriptome survey reveals increased complexity of the alternative splicing landscape in Arabidopsis. Genome Res. 22, 1184–1279 (2012). Genome-wide study revealing a previously unforeseen complexity and prevalence of alternative splicing in plants.
Kazan, K. Alternative splicing and proteome diversity in plants: the tip of the iceberg has just emerged. Trends Plant Sci. 8, 468–471 (2003).
Zhang, X. C. & Gassmann, W. Alternative splicing and mRNA levels of the disease resistance gene RPS4 are induced during defense responses. Plant Physiol. 145, 1577–1587 (2007).
Gassmann, W. Alternative splicing in plant defense. Curr. Top. Microbiol. Immunol. 326, 219–233 (2008).
Mastrangelo, A. M., Marone, D., Laido, G., De Leonardis, A. M. & De Vita, P. Alternative splicing: enhancing ability to cope with stress via transcriptome plasticity. Plant Sci. 185, 40–49 (2012).
Nakaminami, K., Matsui, A., Shinozaki, K. & Seki, M. RNA regulation in plant abiotic stress responses. Biochim. Biophys. Acta 1819, 149–153 (2012).
Sánchez, S. et al. A methyl transferase links the circadian clock to the regulation of alternative splicing. Nature 468, 112–118 (2010). Demonstration that Arg N -methyltransferase 5 (PRMT5) is part of a novel regulatory feedback loop within the circadian clock of plants that regulates alternative splicing of key clock mRNAs.
Arsovski, A. A., Galstyan, A., Guseman, J. M. & Nemhauser, J. L. Photomorphogenesis. Arabidopsis Book 10, e0147 (2012).
Ruckle, M., Burgoon, L., Lawrence, L., Sinkler, C. & Larkin, R. Plastids are major regulators of light signaling in Arabidopsis. Plant Physiol. 159, 366–456 (2012).
Acknowledgements
The authors apologize to those researchers whose work could not be cited owing to space constraints. The work in the authors laboratories was supported by grants to A.R.K. and M.J.M. from the Agencia Nacional de Promoción de Ciencia y Tecnología of Argentina (ANPCYT) and the University of Buenos Aires. A.R.K. is a Senior International Research Scholar of the Howard Hughes Medical Institute. I.E.S and G.D. are recipient of Marie Curie postdoctoral fellowships. M.A. and E.P. are recipients of postdoctoral fellowships and A.R.K. and M.J.M are career investigators from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina (CONICET).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Intron
-
Gene segment that is present in the primary transcript but absent from the mature RNA as a consequence of splicing.
- Cleavage/polyadenylation
-
Endonucleolytic cleavage at the poly(A) site and subsequent addition of a poly(A) tail at the 3′ end of the eukaryotic pre-mRNA. The poly(A) site is defined by the poly(A) signal, which contains the consensus sequence AAUAAA.
- Co-transcriptional
-
Any modification of or addition to the mRNA taking place while it is still being transcribed, that is, before its 3′ end is generated by cleavage/polyadenylation.
- Exons
-
Gene segments that are or can be present in the mature RNA as a consequence of splicing. Because mRNA exons also harbour 5′ and 3′ untranslated regions (UTRs) and genes encoding RNAs other than mRNAs may have introns, exons cannot be simply defined as protein-coding segments.
- Nonsense-mediated mRNA decay
-
(NMD). Mechanism that degrades mRNAs harbouring a premature translational termination codon as a result of gene mutation.
- Capping
-
Addition of 7-methylguanosine nucleotide to the 5′ end of eukaryotic mRNAs.
- Pol II CTD
-
(RNA polymerase II carboxy-terminal domain). This domain consists of a repeating consensus heptad amino acid sequence, Tyr-Ser-Pro-Thr-Ser-Pro-Ser (52 repeats in humans and 26 in yeast). The CTD has important roles in pre-mRNA processing.
- Insulators
-
Sequences that 'isolate' sets of genes co-regulated by the same DNA cis-acting sequences.
- Histone
-
Highly basic nuclear protein that is a structural component of a nucleosome (core histone families H2A, H2B, H3 and H4) or associates with DNA that links nucleosomes (linker histone families H1 and H5).
- Nucleosome
-
Repeating unit of eukaryotic chromatin that consists of a segment of approximately 147 bp of DNA wound around a histone octamer comprising two copies of each core histone (which are H2A, H2B, H3 and H4).
- Warburg effect
-
Metabolic property of cancer cells characterized by energy production through a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by mitochondrial aerobic respiration as in most healthy cells.
Rights and permissions
About this article
Cite this article
Kornblihtt, A., Schor, I., Alló, M. et al. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat Rev Mol Cell Biol 14, 153–165 (2013). https://doi.org/10.1038/nrm3525
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm3525
This article is cited by
-
Deciphering the role of alternative splicing as a potential regulator in fat-tail development of sheep: a comprehensive RNA-seq based study
Scientific Reports (2024)
-
Long-read sequencing reveals the landscape of aberrant alternative splicing and novel therapeutic target in colorectal cancer
Genome Medicine (2023)
-
Mapping intron retention events contributing to complex traits using splice quantitative trait locus
Plant Methods (2023)
-
Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential
Journal of Experimental & Clinical Cancer Research (2023)
-
Transcription elongation factor AtSPT4-2 positively modulates salt tolerance in Arabidopsis thaliana
BMC Plant Biology (2023)
