Abstract
A majority of mammalian and human protein-coding genes undergo alternative splicing with the formation of mRNA isoforms. It was established that 30−40% of the formed mRNA isoforms fell into a special category of bifunctional molecules, “coding−noncoding RNAs.” One possible explanation for the presence of such a large number of unproductive mRNAs is that these molecules are involved in basic processes of gene expression regulation. In this review, the concept of regulated unproductive splicing and translation is considered, which implies a close relationship between the processes of alternative splicing, formation of noncoding mRNA isoforms, and their subsequent degradation, which determines the proportion of productive mRNA transcripts of a gene and the level of its expression in the cell. Modern concepts of noncoding mRNA isoforms of protein-coding genes and their role in the regulation of gene expression under certain physiological and pathophysiological conditions are presented.
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Andrews, S.J. and Rothnagel, J.A., Emerging evidence for functional peptides encoded by short open reading frames, Nat. Rev. Genet., 2014, vol. 15, no. 3, pp. 193–204. doi 10.1038/nrg3520
Mascarenhas, R., Pietrzak, M., Smith, R.M., et al., Allele-selective transcriptome recruitment to polysomes primed for translation: protein-coding and noncoding RNAs, and RNA isoforms, PLoS One, 2015, vol. 10, no. 9. 10. e0136798. doi 10.1371/journal. pone.0136798
Kumari, P. and Sampath, K., cncRNAs: bi-functional RNAs with protein coding and non-coding functions, Semin. Cell Dev. Biol., 2015, vols. 47–48, pp. 40–51. doi 10.1016/j.semcdb.2015.10.024
Gonzalez-Porta, M., Frankish, A., Rung, J., et al., Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene, Genome Biol., 2013, vol. 14, no. 7, p. R70. doi 10.1186/gb-2013-14-7-r70
Wang, D., Zavadil, J., Martin, L., et al., Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis, Mol. Cell. Biol., 2011, vol. 31, no. 17, pp. 3670–3680. doi 10.1128/MCB.05704-11
Hube, F., Velasco, G., Rollin, J., et al., Steroid receptor RNA activator protein binds to and counteracts SRA RNA-mediated activation of MyoD and muscle differentiation, Nucleic Acids Res., 2011, vol. 39, no. 2, pp. 513–525. doi 10.1093/nar/gkq833
Mayba, O., Gilbert, H.N., Liu, J., et al., MBASED: allele-specific expression detection in cancer tissues and cell lines, Genome Biol., 2014, vol. 15, no. 8, p. 405. doi 10.1186/s13059-014-0405-3
Nam, J.-W., Choi, S.-W., and You, B.-H., Incredible RNA: dual functions of coding and noncoding, Mol. Cells, 2016, vol. 39, no. 5, pp. 367–374. doi 10.14348/molcells.2016.0039
Karapetyan, A.R., Buiting, C., Kuiper, R.A., and Coolen, M.W., Regulatory roles for long ncRNA and mRNA, Cancers, 2013, vol. 5, no. 2, pp. 462–490. doi 10.3390/cancers5020462
Cheng, H., Chan, W.S., Li, Z., et al., Small open reading frames: current prediction techniques and future prospect, Curr. Protein Pept. Sci., 2011, vol. 12, no. 6, pp. 503–507.
Mackowiak, S.D., Zauber, H., Bielow, C., et al., Extensive identification and analysis of conserved small ORFs in animals, Genome Biol., 2015, vol. 16, p. 179. doi 10.1186/s13059-015-0742-x
Anderson, D.M., Anderson, K.M., Chang, C.-L., et al., A micropeptide encoded by a putative long noncoding RNA regulates muscle performance, Cell, 2015, vol. 160, no. 4, pp. 595–606. doi 10.1016/j.cell.2015.01.009
Jenny, A., Hachet, O., Zavorszky, P., et al., A translation-independent role of oskar RNA in early Drosophila oogenesis, Dev. Camb. Engl., 2006, vol. 133, no. 15, pp. 2827–2833. doi 10.1242/dev.02456
Lim, S., Kumari, P., Gilligan, P., et al., Dorsal activity of maternal squint is mediated by a non-coding function of the RNA, Dev. Camb. Engl., 2012, vol. 139, no. 16, pp. 2903–2915. doi 10.1242/dev.077081
Wan, Y., Qu, K., Ouyang, Z., et al., Genome-wide measurement of RNA folding energies, Mol. Cell., 2012, vol. 48, no. 2, pp. 169–181. doi 10.1016/j.molcel. 2012.08.008
Young, T.M., Tsai, M., Tian, B., et al., Cellular mRNA activates transcription elongation by displacing 7SK RNA, PLoS One, 2007, vol. 2, no. 10. e1010. doi 10.1371/journal.pone.0001010
Rivas, M.A., Pirinen, M., Conrad, D.F., et al., Impact of predicted protein-truncating genetic variants on the human transcriptome, Science, 2015, vol. 348, no. 6235, pp. 666–669. doi 10.1126/science.1261877
Lappalainen, T., Sammeth, M., Friedländer, M.R., et al., Transcriptome and genome sequencing uncovers functional variation in humans, Nature, 2013, vol. 501, no. 7468, pp. 506–511. doi 10.1038/nature12531
Holbrook, J.A., Neu-Yilik, G., Hentze, M.W., and Kulozik, A.E., Nonsense-mediated decay approaches the clinic, Nat. Genet., 2004, vol. 36, no. 8, pp. 801–808. doi 10.1038/ng1403
Cohen, J.C., Boerwinkle, E., Mosley, T.H., and Hobbs, H.H., Sequence variations in PCSK9, low LDL, and protection against coronary heart disease, N. Engl. J. Med., 2006, vol. 354, no. 12, pp. 1264–1272. doi 10.1056/NEJMoa054013
Nilsen, T.W. and Graveley, B.R., Expansion of the eukaryotic proteome by alternative splicing, Nature, 2010, vol. 463, no. 7280, pp. 457–463. doi 10.1038/nature08909
van den Hoogenhof, M.M.G., Pinto, Y.M., and Creemers, E.E., RNA splicing: regulation and dysregu lation in the heart, Circ. Res., 2016, vol. 118, no. 3, pp. 454–468. doi 10.1161/CIRCRESAHA.115.307872
Barbosa-Morais, N.L., Irimia, M., Pan, Q., et al., The evolutionary landscape of alternative splicing in vertebrate species, Science, 2012, vol. 338, no. 6114, pp. 1587–1593. doi 10.1126/science.1230612
Merkin, J., Russell, C., Chen, P., and Burge, C.B., Evolutionary dynamics of gene and isoform regulation in mammalian tissues, Science, 2012, vol. 338, no. 6114, pp. 1593–1599. doi 10.1126/science.1228186
Pan, Q., Shai, O., Lee, L.J., et al., Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing, Nat. Genet., 2008, vol. 40, no. 12, pp. 1413–1415. doi 10.1038/ng.259
Wang, E.T., Sandberg, R., Luo, S., et al., Alternative isoform regulation in human tissue transcriptomes, Nature, 2008, vol. 456, no. 7221, pp. 470–476. doi 10.1038/nature07509
Graveley, B.R., Sorting out the complexity of SR protein functions, RNA, 2000, vol. 6, no. 9, pp. 1197–1211.
Lin, S. and Fu, X.-D., SR proteins and related factors in alternative splicing, Adv. Exp. Med. Biol., 2007, vol. 623, pp. 107–122.
Gerstberger, S., Hafner, M., and Tuschl, T., A census of human RNA-binding proteins, Nat. Rev. Genet., 2014, vol. 15, no. 12, pp. 829–845.
Eperon, I.C., Makarova, O.V., Mayeda, A., et al., Selection of alternative 5′ splice sites: role of U1 snRNP and models for the antagonistic effects of SF2/ASF and hnRNP A1, Mol. Cell. Biol., 2000, vol. 20, no. 22, pp. 8303–8318.
Hall, M.P., Nagel, R.J., Fagg, W.S., et al., Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation, RNA, 2013, vol. 19, no. 5, pp. 627–638. doi 10.1261/rna.038422.113
Hanamura, A., Caceres, J.F., Mayeda, A., et al., Regulated tissue-specific expression of antagonistic premRNA splicing factors, RNA, 1998, vol. 4, no. 4, pp. 430–444.
Kalsotra, A., Xiao, X., Ward, A.J., et al., A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 51, pp. 20333–20338. doi 10.1073/pnas.0809045105
Kim, E., Goren, A., and Ast, G., Alternative splicing: current perspectives, BioEssays News Rev. Mol. Cell. Dev. Biol., 2008, vol. 30, no. 1, pp. 38–47. doi 10.1002/bies.20692
Garcia, J., Gerber, S.H., Sugita, S., et al., A conformational switch in the Piccolo C2A domain regulated by alternative splicing, Nat. Struct. Mol. Biol., 2004, vol. 11, no. 1, pp. 45–53. doi 10.1038/nsmb707
Resch, A., Xing, Y., Modrek, B., et al., Assessing the impact of alternative splicing on domain interactions in the human proteome, J. Proteome Res., 2004, vol. 3, no. 1, pp. 76–83.
Clark, F. and Thanaraj, T.A., Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human, Hum. Mol. Genet., 2002, vol. 11, no. 4, pp. 451–464.
Hillman, R.T., Green, R.E., and Brenner, S.E., An unappreciated role for RNA surveillance, Genome Biol., 2004, vol. 5, no. 2. R8. doi 10.1186/gb-2004-5-2-r8
Nagy, E. and Maquat, L.E., A rule for terminationcodon position within intron-containing genes: when nonsense affects RNA abundance, Trends Biochem. Sci., 1998, vol. 23, no. 6, pp. 198–199.
Soergel, D.A.W., Lareau, L.F., and Brenner, S.E., Regulation of Gene Expression by Coupling of Alternative Splicing and NMD, Landes Bioscience, 2013. https://doi.org/www.ncbi.nlm.nih.gov/book/NBK6088/.
Lewis, B.P., Green, R.E., and Brenner, S.E., Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 1, pp. 189–192.
Green, R.E., Lewis, B.P., Hillman, R.T., et al., Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes, Bioinf. Oxf. Engl., 2003, vol. 19, suppl. 1, pp. i118–i121.
Conti, E. and Izaurralde, E., Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species, Curr. Opin. Cell Biol., 2005, vol. 17, no. 3, pp. 316–325. doi 10.1016/j.ceb.2005.04.005
Staiger, D., Zecca, L., Wieczorek Kirk, D.A., et al., The circadian clock regulated RNA-binding protein AtGRP7 autoregulates its expression by influencing alternative splicing of its own pre-mRNA, Plant J. Cell Mol. Biol., 2003, vol. 33, no. 2, pp. 361–371.
Vilardell, J., Chartrand, P., Singer, R.H., and Warner, J.R., The odyssey of a regulated transcript, RNA, 2000, vol. 6, no. 12, pp. 1773–1780.
Horikawa, Y., Oda, N., Cox, N.J., et al., Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus, Nat. Genet., 2000, vol. 26, no. 2, pp. 163–175. doi 10.1038/79876
Baier, L.J., Permana, P.A., Yang, X., et al., A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance, J. Clin. Invest., 2000, vol. 106, no. 7, pp. R69–R73.
Lamba, J.K., Adachi, M., Sun, D., et al., Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons, Hum. Mol. Genet., 2003, vol. 12, no. 3, pp. 99–109.
Skandalis, A. and Uribe, E., A survey of splice variants of the human hypoxanthine phosphoribosyl transferase and DNA polymerase beta genes: products of alternative or aberrant splicing?, Nucleic Acids Res., 2004, vol. 32, no. 22, pp. 6557–6564. doi 10.1093/nar/gkh967
Chan, W.-K., Huang, L., Gudikote, J.P., et al., An alternative branch of the nonsense-mediated decay pathway, EMBO J., 2007, vol. 26, no. 7, pp. 1820–1830. doi 10.1038/sj.emboj.7601628
Fatscher, T., Boehm, V., and Gehring, N.H., Mechanism, factors, and physiological role of nonsensemediated mRNA decay, Cell. Mol. Life Sci., 2015, vol. 72, no. 23, pp. 4523–4544. doi 10.1007/s00018-015-2017-9
Pacheco, T.R., Gomes, A.Q., Barbosa-Morais, N.L., et al., Diversity of vertebrate splicing factor U2AF35: identification of alternatively spliced U2AF1 mRNAs, J. Biol. Chem., 2004, vol. 279, no. 26, pp. 27039–27049. doi 10.1074/jbc.M402136200
Winter, J., Lehmann, T., Krauss, S., et al., Regulation of the MID1 protein function is fine-tuned by a complex pattern of alternative splicing, Hum. Genet., 2004, vol. 114, no. 6, pp. 541–552. doi 10.1007/s00439-004-1114-x
Dreumont, N., Maresca, A., Boisclair-Lachance, J.-F., et al., A minor alternative transcript of the fumarylacetoacetate hydrolase gene produces a protein despite being likely subjected to nonsense-mediated mRNA decay, BMC Mol. Biol., 2005, vol. 6, p. 1. doi 10.1186/1471-2199-6-1
Confaloni, A., Crestini, A., Albani, D., et al., Rat nicastrin gene: cDNA isolation, mRNA variants and expression pattern analysis, Brain Res. Mol. Brain Res., 2005, vol. 136, nos. 1–2, pp. 12–22. doi 10.1016/j.molbrainres. 2004.12.022
Wollerton, M.C., Gooding, C., Wagner, E.J., et al., Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay, Mol. Cell, 2004, vol. 13, no. 1, pp. 91–100.
Spellman, R., Rideau, A., Matlin, A., et al., Regulation of alternative splicing by PTB and associated factors, Biochem. Soc. Trans., 2005, vol. 33, no. 3, pp. 457–460. doi 10.1042/BST0330457
Sureau, A., Gattoni, R., Dooghe, Y., et al., SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs, EMBO J., 2001, vol. 20, no. 7, pp. 1785–1796. doi 10.1093/emboj/20.7.1785
Stoilov, P., Daoud, R., Nayler, O., and Stamm, S., Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its premRNA, Hum. Mol. Genet., 2004, vol. 13, no. 5, pp. 509–524. doi 10.1093/hmg/ddh051
Le Guiner, C., Gesnel, M.-C., and Breathnach, R., TIA-1 or TIAR is required for DT40 cell viability, J. Biol. Chem., 2003, vol. 278, no. 12, pp. 10465–10476. doi 10.1074/jbc.M212378200
Wilson, G.M., Sun, Y., Sellers, J., et al., Regulation of AUF1 expression via conserved alternatively spliced elements in the 3′ untranslated region, Mol. Cell. Biol., 1999, vol. 19, no. 6, pp. 4056–4064.
Menegay, H.J., Myers, M.P., Moeslein, F.M., and Landreth, G.E., Biochemical characterization and localization of the dual specificity kinase CLK1, J. Cell Sci., 2000, vol. 113, part 18, pp. 3241–3253.
Lim, K.H., Ferraris, L., Filloux, M.E., et al., Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes, Proc. Natl. Acad. Sci. U.S.A., 2011, vol. 108, no. 27, pp. 11093–11098. doi 10.1073/pnas.1101135108
Wang, G.-S. and Cooper, T.A., Splicing in disease: disruption of the splicing code and the decoding machinery, Nat. Rev. Genet., 2007, vol. 8, no. 10, pp. 749–761. doi 10.1038/nrg2164
Bedwell, D.M., Kaenjak, A., Benos, D.J., et al., Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line, Nat. Med., 1997, vol. 3, no. 11, pp. 1280–1284.
Liang, F., Shang, H., Jordan, N.J., et al., Highthroughput screening for readthrough modulators of CFTR PTC mutations, SLAS Technol., 2017, vol. 22, no. 3, pp. 315–324. doi 10.1177/2472630317692561
Clancy, J.P., Bebok, Z., Ruiz, F., et al., Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis, Am. J. Respir. Crit. Care Med., 2001, vol. 163, no. 7, pp. 1683–1692. doi 10.1164/ajrccm.163.7.2004001
Barton-Davis, E.R., Cordier, L., Shoturma, D.I., et al., Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice, J. Clin. Invest., 1999, vol. 104, no. 4, pp. 375–381.
Politano, L., Nigro, G., Nigro, V., et al., Gentamicin administration in Duchenne patients with premature stop codon: preliminary results, Acta Myol. Myopathies Cardiomyopathies: Off. J. Mediterr. Soc. Myol., 2003, vol. 22, no. 1, pp. 15–21.
Mankodi, A., Takahashi, M.P., Jiang, H., et al., Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy, Mol. Cell, 2002, vol. 10, no. 1, pp. 35–44.
Vittal, P., Pandya, S., Sharp, K., et al., Antisense FMR1 splice variant and loss of AGG interruptions are predictors of Fragile X-associated tremor/ataxia syndrome (FXTAS) (P3.002), Neurology, 2017, vol. 88, no. 16, suppl., p. 3.002.
Kumari, D. and Usdin, K., Is Friedreich ataxia an epigenetic disorder?, Clin. Epigenet., 2012, vol. 4, no. 1, p. 2. doi 10.1186/1868-7083-4-2
Wongtrakoongate, P., Riddick, G., Fucharoen, S., et al., Association of the long non-coding RNA steroid receptor RNA activator (SRA) with TrxG and PRC2 complexes, PLoS Genet., 2015, vol. 11, no. 10. e1005615. doi 10.1371/journal.pgen.1005615
Sampath, K. and Ephrussi, A., cncRNAs: RNAs with both coding and non-coding roles in development, Development, 2016, vol. 143, no. 8, pp. 1234–1241. doi 10.1242/dev.133298
Leygue, E., Dotzlaw, H., Watson, P.H., et al., Expression of the steroid receptor RNA activator in human breast tumors, Cancer Res., 1999, vol. 59, no. 17, pp. 4190–4193.
Murphy, L.C., Simon, S.L., Parkes, A., et al., Altered expression of estrogen receptor coregulators during human breast tumorigenesis, Cancer Res., 2000, vol. 60, no. 22, pp. 6266–6271.
Gardner, L.B., Nonsense mediated RNA decay regulation by cellular stress; implications for tumorigenesis, Mol. Cancer Res., 2010, vol. 8, no. 3, pp. 295–308. doi 10.1158/1541-7786.MCR-09-0502
Perrin-Vidoz, L., Sinilnikova, O.M., Stoppa-Lyonnet, D., et al., The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons, Hum. Mol. Genet., 2002, vol. 11, no. 33, pp. 2805–2814.
Kawasaki, T., Tomita, Y., Watanabe, R., et al., mRNA and protein expression of p53 mutations in human bladder cancer cell lines, Cancer Lett., 1994, vol. 82, no. 1, pp. 113–121.
Liu, C., Karam, R., Zhou, Y., et al., The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma, Nat. Med., 2014, vol. 82, no. 1, pp. 596–598.
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Original Russian Text © E.N. Filatova, O.V. Utkin, 2018, published in Genetika, 2018, Vol. 54, No. 8, pp. 869–878.
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Filatova, E.N., Utkin, O.V. The Role of Noncoding mRNA Isoforms in the Regulation of Gene Expression. Russ J Genet 54, 879–887 (2018). https://doi.org/10.1134/S1022795418080057
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DOI: https://doi.org/10.1134/S1022795418080057