Abstract
Alternative splicing represents an important level of the regulation of gene function in eukaryotic organisms. It plays a critical role in virtually every biological process within an organism, including regulation of cell division and cell death, differentiation of tissues in the embryo and the adult organism, as well as in cellular response to diverse environmental factors. In turn, studies of the last decade have shown that alternative splicing itself is controlled by different mechanisms. Unfortunately, there is no clear understanding of how these diverse mechanisms, or determinants, regulate and constrain the set of alternative RNA species produced from any particular gene in every cell of the human body. Here, we provide a consolidated overview of alternative splicing determinants including RNA–protein interactions, epigenetic regulation via chromatin remodeling, coupling of transcription-to-alternative splicing, effect of secondary structures in pre-RNA, and function of the RNA quality control systems. We also extensively and critically discuss some mechanistic insights on coordinated inclusion/exclusion of exons during the formation of mature RNA molecules. We conclude that the final structure of RNA is pre-determined by a complex interplay between cis- and trans-acting factors. Altogether, currently available empirical data significantly expand our understanding of the functioning of the alternative splicing machinery of cells in normal and pathological conditions. On the other hand, there are still many blind spots that require further deep investigations.
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References
Alexander RD, Innocente SA, Barrass JD, Beggs JD (2010) Splicing-dependent RNA polymerase pausing in yeast. Mol Cell 40:582–593. doi:10.1016/j.molcel.2010.11.005
Alló M, Buggiano V, Fededa JP et al (2009) Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat Struct Mol Biol 16:717–724. doi:10.1038/nsmb.1620
Alonso CR (2012) A complex “mRNA degradation code” controls gene expression during animal development. Trends Genet TIG 28:78–88. doi:10.1016/j.tig.2011.10.005
Arbel-Goren R, Tal A, Stavans J (2014) Phenotypic noise: effects of post-transcriptional regulatory processes affecting mRNA. Wiley Interdiscip Rev RNA 5:197–207. doi:10.1002/wrna.1209
Auboeuf D, Hönig A, Berget SM, O’Malley BW (2002) Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298:416–419. doi:10.1126/science.1073734
Auboeuf D, Dowhan DH, Kang YK et al (2004) Differential recruitment of nuclear receptor coactivators may determine alternative RNA splice site choice in target genes. Proc Natl Acad Sci USA 101:2270–2274
Aversa R, Sorrentino A, Esposito R et al (2016) Alternative splicing in adhesion- and motility-related genes in breast cancer. Int J Mol Sci. doi:10.3390/ijms17010121
Badr E, ElHefnawi M, Heath LS (2016) Computational identification of tissue-specific splicing regulatory elements in human genes from RNA-Seq data. PLoS One. doi:10.1371/journal.pone.0166978
Baraniak AP, Lasda EL, Wagner EJ, Garcia-Blanco MA (2003) A stem structure in fibroblast growth factor receptor 2 transcripts mediates cell-type-specific splicing by approximating intronic control elements. Mol Cell Biol 23:9327–9337. doi:10.1128/MCB.23.24.9327-9337.2003
Barresi S, Tomaselli S, Athanasiadis A et al (2014) Oligophrenin-1 (OPHN1), a gene involved in X-linked intellectual disability, undergoes RNA editing and alternative splicing during human brain development. PLoS One 9(3):e91351. doi:10.1371/journal.pone.0091351
Barry G, Briggs JA, Vanichkina DP et al (2014) The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry 19:486–494. doi:10.1038/mp.2013.45
Beghini A, Ripamonti CB, Peterlongo P et al (2000) RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. Hum Mol Genet 9:2297–2304
Bieberstein NI, Carrillo Oesterreich F, Straube K, Neugebauer KM (2012) First exon length controls active chromatin signatures and transcription. Cell Rep 2:62–68. doi:10.1016/j.celrep.2012.05.019
Bieberstein NI, Kozáková E, Huranová M et al (2016) TALE-directed local modulation of H3K9 methylation shapes exon recognition. Sci Rep. doi:10.1038/srep29961
Bitton DA, Atkinson SR, Rallis C et al (2015) Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast. Genome Res 25:884–896. doi:10.1101/gr.185371.114
Bolisetty MT, Rajadinakaran G, Graveley BR (2015) Determining exon connectivity in complex mRNAs by nanopore sequencing. Genome Biol. doi:10.1186/s13059-015-0777-z
Boutz PL, Stoilov P, Li Q et al (2007) A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev 21:1636–1652. doi:10.1101/gad.1558107
Braunschweig U, Gueroussov S, Plocik A et al (2013) Dynamic integration of splicing within gene regulatory pathways. Cell 152:1252–1269. doi:10.1016/j.cell.2013.02.034
Braunschweig U, Barbosa-Morais NL, Pan Q et al (2014) Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res 24:1774–1786. doi:10.1101/gr.177790.114
Buckley PT, Khaladkar M, Kim J, Eberwine J (2014) Cytoplasmic intron retention, function, splicing, and the sentinel RNA hypothesis. Wiley Interdiscip Rev RNA 5:223–230. doi:10.1002/wrna.1203
Buratti E, Muro AF, Giombi M et al (2004) RNA folding affects the recruitment of sr proteins by mouse and human polypurinic enhancer elements in the fibronectin EDA exon. Mol Cell Biol 24:1387–1400. doi:10.1128/MCB.24.3.1387-1400.2004
Carrillo Oesterreich F, Preibisch S, Neugebauer KM (2010) Global analysis of nascent RNA reveals transcriptional pausing in terminal exons. Mol Cell 40:571–581. doi:10.1016/j.molcel.2010.11.004
Carrillo Oesterreich F, Herzel L, Straube K et al (2016) Splicing of nascent RNA coincides with intron exit from RNA polymerase II. Cell 165:372–381. doi:10.1016/j.cell.2016.02.045
Chabot B, Shkreta L (2016) Defective control of pre–messenger RNA splicing in human disease. J Cell Biol 212:13–27. doi:10.1083/jcb.201510032
Chathoth KT, Barrass JD, Webb S, Beggs JD (2014) A splicing-dependent transcriptional checkpoint associated with prespliceosome formation. Mol Cell 53:779–790. doi:10.1016/j.molcel.2014.01.017
Chen L (2010) A global comparison between nuclear and cytosolic transcriptomes reveals differential compartmentalization of alternative transcript isoforms. Nucleic Acids Res 38:1086–1097. doi:10.1093/nar/gkp1136
Chen M, Manley JL (2009) Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 10:741–754. doi:10.1038/nrm2777
Cheng J, Maquat LE (1993) Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol Cell Biol 13:1892–1902
Conze T, Göransson J, Razzaghian HR et al (2010) Single molecule analysis of combinatorial splicing. Nucleic Acids Res 38:e163. doi:10.1093/nar/gkq581
Corvelo A, Hallegger M, Smith CWJ, Eyras E (2010) Genome-wide association between branch point properties and alternative splicing. PLoS Comput Biol. doi:10.1371/journal.pcbi.1001016
Dai C, Li W, Liu J, Zhou XJ (2012) Integrating many co-splicing networks to reconstruct splicing regulatory modules. BMC Syst Biol 6:S17. doi:10.1186/1752-0509-6-S1-S17
Das R, Yu J, Zhang Z et al (2007) SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol Cell 26:867–881. doi:10.1016/j.molcel.2007.05.036
Davis-Turak JC, Allison K, Shokhirev MN et al (2015) Considering the kinetics of mRNA synthesis in the analysis of the genome and epigenome reveals determinants of co-transcriptional splicing. Nucleic Acids Res 43:699–707. doi:10.1093/nar/gku1338
de Almeida SF, García-Sacristán A, Custódio N, Carmo-Fonseca M (2010) A link between nuclear RNA surveillance, the human exosome and RNA polymerase II transcriptional termination. Nucleic Acids Res 38:8015–8026. doi:10.1093/nar/gkq703
De Conti L, Baralle M, Buratti E (2013) Exon and intron definition in pre-mRNA splicing. Wiley Interdiscip Rev RNA 4:49–60. doi:10.1002/wrna.1140
de la Mata M, Muñoz MJ, Alló M et al (2011) RNA polymerase II elongation at the crossroads of transcription and alternative splicing. Genet Res Int. doi:10.4061/2011/309865
Denis MM, Tolley ND, Bunting M et al (2005) Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122:379–391. doi:10.1016/j.cell.2005.06.015
Dou Y, Fox-Walsh KL, Baldi PF, Hertel KJ (2006) Genomic splice-site analysis reveals frequent alternative splicing close to the dominant splice site. RNA 12:2047–2056. doi:10.1261/rna.151106
Dredge BK, Stefani G, Engelhard CC, Darnell RB (2005) Nova autoregulation reveals dual functions in neuronal splicing. EMBO J 24:1608–1620. doi:10.1038/sj.emboj.7600630
Dujardin G, Lafaille C, de la Mata M et al (2014) How slow RNA polymerase II elongation favors alternative exon skipping. Mol Cell 54:683–690. doi:10.1016/j.molcel.2014.03.044
Dutertre M, Sanchez G, Barbier J et al (2011) The emerging role of pre-messenger RNA splicing in stress responses: sending alternative messages and silent messengers. RNA Biol 8:740–747. doi:10.4161/rna.8.5.16016
Emerick MC, Parmigiani G, Agnew WS (2007) Multivariate analysis and visualization of splicing correlations in single-gene transcriptomes. BMC Bioinform 8:16. doi:10.1186/1471-2105-8-16
Eswaran J, Horvath A, Godbole S et al (2013) RNA sequencing of cancer reveals novel splicing alterations. Sci Rep. doi:10.1038/srep01689
Evsyukova I, Bradrick SS, Gregory SG, Garcia-Blanco MA (2013) Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA 19:103–115. doi:10.1261/rna.035410.112
Faigenbloom L, Rubinstein ND, Kloog Y et al (2015) Regulation of alternative splicing at the single-cell level. Mol Syst Biol. doi:10.15252/msb.20156278
Fededa JP, Petrillo E, Gelfand MS et al (2005) A polar mechanism coordinates different regions of alternative splicing within a single gene. Mol Cell 19:393–404. doi:10.1016/j.molcel.2005.06.035
Fisette J-F, Toutant J, Dugré-Brisson S et al (2010) hnRNP A1 and hnRNP H can collaborate to modulate 5′ splice site selection. RNA 16:228–238. doi:10.1261/rna.1890310
Fong N, Bentley DL (2001) Capping, splicing, and 3′ processing are independently stimulated by RNA polymerase II: different functions for different segments of the CTD. Genes Dev 15:1783–1795. doi:10.1101/gad.889101
Fox-Walsh KL, Hertel KJ (2009) Splice-site pairing is an intrinsically high fidelity process. Proc Natl Acad Sci USA 106:1766–1771. doi:10.1073/pnas.0813128106
Fox-Walsh KL, Dou Y, Lam BJ et al (2005) The architecture of pre-mRNAs affects mechanisms of splice-site pairing. Proc Natl Acad Sci USA 102:16176–16181. doi:10.1073/pnas.0508489102
Fuchs G, Hollander D, Voichek Y et al (2014) Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate. Genome Res 24:1572–1583. doi:10.1101/gr.176487.114
Galante PAF, Sakabe NJ, Kirschbaum-Slager N, Souza SJD (2004) Detection and evaluation of intron retention events in the human transcriptome. RNA 10:757–765. doi:10.1261/rna.5123504
Galej WP, Nguyen THD, Newman AJ, Nagai K (2014) Structural studies of the spliceosome: zooming into the heart of the machine. Curr Opin Struct Biol 25:57–66. doi:10.1016/j.sbi.2013.12.002
Garcia-Blanco MA, Baraniak AP, Lasda EL (2004) Alternative splicing in disease and therapy. Nat Biotechnol 22:535–546. doi:10.1038/nbt964
Gazzoli I, Pulyakhina I, Verwey NE et al (2015) Non-sequential and multi-step splicing of the dystrophin transcript. RNA Biol 13:290–305. doi:10.1080/15476286.2015.1125074
Ge Y, Porse BT (2014) The functional consequences of intron retention: alternative splicing coupled to NMD as a regulator of gene expression. BioEssays News Rev Mol Cell Dev Biol 36:236–243. doi:10.1002/bies.201300156
Geissler R, Simkin A, Floss D et al (2016) A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1. Genes Dev 30:1070–1085. doi:10.1101/gad.277392.116
Gonzalez I, Munita R, Agirre E et al (2015) A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature. Nat Struct Mol Biol 22:370–376. doi:10.1038/nsmb.3005
Goren A, Kim E, Amit M et al (2010) Overlapping splicing regulatory motifs—combinatorial effects on splicing. Nucleic Acids Res 38:3318–3327. doi:10.1093/nar/gkq005
Graveley BR (2005) Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123:65–73. doi:10.1016/j.cell.2005.07.028
Grinev VV, Migas AA, Kirsanava AD et al (2015) Decoding of exon splicing patterns in the human RUNX1-RUNX1T1 fusion gene. Int J Biochem Cell Biol 68:48–58. doi:10.1016/j.biocel.2015.08.017
Guantes R, Rastrojo A, Neves R et al (2015) Global variability in gene expression and alternative splicing is modulated by mitochondrial content. Genome Res 25:633–644. doi:10.1101/gr.178426.114
Gueroussov S, Gonatopoulos-Pournatzis T, Irimia M et al (2015) An alternative splicing event amplifies evolutionary differences between vertebrates. Science 349:868–873. doi:10.1126/science.aaa8381
Gunderson FQ, Merkhofer EC, Johnson TL (2011) Dynamic histone acetylation is critical for cotranscriptional spliceosome assembly and spliceosomal rearrangements. Proc Natl Acad Sci USA 108:2004–2009. doi:10.1073/pnas.1011982108
Han A, Stoilov P, Linares AJ et al (2014) De novo prediction of PTBP1 binding and splicing targets reveals unexpected features of its RNA recognition and function. PLoS Comput Biol. doi:10.1371/journal.pcbi.1003442
Hao S, Baltimore D (2013) RNA splicing regulates the temporal order of TNF-induced gene expression. Proc Natl Acad Sci USA 110:11934–11939. doi:10.1073/pnas.1309990110
Hatton AR, Subramaniam V, Lopez AJ (1998) Generation of alternative ultrabithorax isoforms and stepwise removal of a large intron by resplicing at exon–exon junctions. Mol Cell 2:787–796. doi:10.1016/S1097-2765(00)80293-2
Hendrickson DG, Kelley DR, Tenen D et al (2016) Widespread RNA binding by chromatin-associated proteins. Genome Biol. doi:10.1186/s13059-016-0878-3
Hiller M, Zhang Z, Backofen R, Stamm S (2007) Pre-mRNA secondary structures influence exon recognition. PLoS Genet. doi:10.1371/journal.pgen.0030204
Hilleren PJ, Parker R (2003) Cytoplasmic degradation of splice-defective pre-mRNAs and intermediates. Mol Cell 12:1453–1465
Hnilicová J, Hozeifi S, Dušková E et al (2011) Histone deacetylase activity modulates alternative splicing. PLoS One. doi:10.1371/journal.pone.0016727
Hodges C, Bintu L, Lubkowska L et al (2009) Nucleosomal fluctuations govern the transcription dynamics of RNA polymerase II. Science 325:626–628. doi:10.1126/science.1172926
Hsu S-N, Hertel KJ (2009) Spliceosomes walk the line: splicing errors and their impact on cellular function. RNA Biol 6:526–530
Huang S-C, Cho A, Norton S et al (2009) Coupled transcription-splicing regulation of mutually exclusive splicing events at the 5′ exons of protein 4.1R gene. Blood 114:4233–4242. doi:10.1182/blood-2009-02-206219
Huelga SC, Vu AQ, Arnold JD et al (2012) Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep 1:167–178. doi:10.1016/j.celrep.2012.02.001
Hug N, Longman D, Cáceres JF (2016) Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res 44:1483–1495. doi:10.1093/nar/gkw010
Iancu OD, Colville A, Oberbeck D et al (2015) Cosplicing network analysis of mammalian brain RNA-Seq data utilizing WGCNA and Mantel correlations. Front Genet. doi:10.3389/fgene.2015.00174
Iijima T, Hidaka C, Iijima Y-H (2016) Spatio-temporal regulations and functions of neuronal alternative RNA splicing in developing and adult brains. Neurosci Res. doi:10.1016/j.neures.2016.01.010
Isken O, Maquat LE (2007) Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Genes Dev 21:1833–3856. doi:10.1101/gad.1566807
Isken O, Maquat LE (2008) The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nat Rev Genet 9:699–712. doi:10.1038/nrg2402
Jangi M, Sharp PA (2014) Building robust transcriptomes with master splicing factors. Cell 159:487–498. doi:10.1016/j.cell.2014.09.054
Jimeno-González S, Payán-Bravo L, Muñoz-Cabello AM et al (2015) Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing. Proc Natl Acad Sci USA 112:14840–14845. doi:10.1073/pnas.1506760112
Johnson MB, Kawasawa YI, Mason CE et al (2009) Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron 62:494–509. doi:10.1016/j.neuron.2009.03.027
Kalantari R, Chiang C-M, Corey DR (2016) Regulation of mammalian transcription and splicing by Nuclear RNAi. Nucleic Acids Res 44:524–537. doi:10.1093/nar/gkv1305
Kalsotra A, Cooper TA (2011) Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet 12:715–729. doi:10.1038/nrg3052
Kameoka S, Duque P, Konarska MM (2004) p54nrb associates with the 5′ splice site within large transcription/splicing complexes. EMBO J 23:1782–1791. doi:10.1038/sj.emboj.7600187
Kar A, Fushimi K, Zhou X et al (2011) RNA helicase p68 (DDX5) regulates tau exon 10 splicing by modulating a stem-loop structure at the 5′ splice site. Mol Cell Biol 31:1812–1821. doi:10.1128/MCB.01149-10
Ke S, Chasin LA (2011) Context-dependent splicing regulation. RNA Biol 8:384–388. doi:10.4161/rna.8.3.14458
Kelly S, Georgomanolis T, Zirkel A et al (2015) Splicing of many human genes involves sites embedded within introns. Nucleic Acids Res 43:4721–4732. doi:10.1093/nar/gkv386
Keren-Shaul H, Lev-Maor G, Ast G (2013) Pre-mRNA splicing is a determinant of nucleosome organization. PLoS One. doi:10.1371/journal.pone.0053506
Kervestin S, Jacobson A (2012) NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 13:700–712. doi:10.1038/nrm3454
Kim H-J, Seol J-H, Han J-W et al (2007) Histone chaperones regulate histone exchange during transcription. EMBO J 26:4467–4474. doi:10.1038/sj.emboj.7601870
Kim S, Kim H, Fong N et al (2011) Pre-mRNA splicing is a determinant of histone H3K36 methylation. Proc Natl Acad Sci USA 108:13564–13569. doi:10.1073/pnas.1109475108
Klauer AA, van Hoof A (2012) Degradation of mRNAs that lack a stop codon: a decade of nonstop progress. Wiley Interdiscip Rev RNA 3:649–660. doi:10.1002/wrna.1124
Konermann S, Brigham MD, Trevino AE et al (2015) Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517:583–588. doi:10.1038/nature14136
Kornblihtt AR (2005) Promoter usage and alternative splicing. Curr Opin Cell Biol 17:262–268. doi:10.1016/j.ceb.2005.04.014
Kornblihtt AR, Pesce CG, Alonso CR et al (1996) The fibronectin gene as a model for splicing and transcription studies. FASEB J Off Publ Fed Am Soc Exp Biol 10:248–257
Kornblihtt AR, de la Mata M, Fededa JP et al (2004) Multiple links between transcription and splicing. RNA 10:1489–1498. doi:10.1261/rna.7100104
Kornblihtt AR, Schor IE, Alló M et al (2013) Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat Rev Mol Cell Biol 14:153–165. doi:10.1038/nrm3525
Kovacs E, Tompa P, Liliom K, Kalmar L (2010) Dual coding in alternative reading frames correlates with intrinsic protein disorder. Proc Natl Acad Sci 107:5429–5434. doi:10.1073/pnas.0907841107
Kralovicova J, Patel A, Searle M, Vorechovsky I (2015) The role of short RNA loops in recognition of a single-hairpin exon derived from a mammalian-wide interspersed repeat. RNA Biol 12:54–69. doi:10.1080/15476286.2015.1017207
Kurosaki T, Maquat LE (2016) Nonsense-mediated mRNA decay in humans at a glance. J Cell Sci 129:461–467. doi:10.1242/jcs.181008
Lareau LF, Brenner SE (2015) Regulation of splicing factors by alternative splicing and NMD is conserved between kingdoms yet evolutionarily flexible. Mol Biol Evol 32:1072–1079. doi:10.1093/molbev/msv002
Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84:291–323. doi:10.1146/annurev-biochem-060614-034316
LeGault LH, Dewey CN (2013) Inference of alternative splicing from RNA-Seq data with probabilistic splice graphs. Bioinformatics 29:2300–2310. doi:10.1093/bioinformatics/btt396
Lejeune F (2017) Nonsense-mediated mRNA decay at the crossroads of many cellular pathways. BMB Rep 50:175–185. doi:10.5483/BMBRep.2017.50.4.015
Lenasi T, Peterlin BM, Dovc P (2006) Distal regulation of alternative splicing by splicing enhancer in equine beta-casein intron 1. RNA N Y N 12:498–507. doi:10.1261/rna.7261206
Lev-Maor G, Ram O, Kim E et al (2008) Intronic Alus influence alternative splicing. PLoS Genet. doi:10.1371/journal.pgen.1000204
Li W, Dai C, Kang S, Zhou XJ (2014) Integrative analysis of many RNA-seq datasets to study alternative splicing. Methods 67:313–324. doi:10.1016/j.ymeth.2014.02.024
Li S, Garrett-Bakelman FE, Chung SS et al (2016) Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med 22:792–799. doi:10.1038/nm.4125
Lin L, Minard LV, Johnston GC et al (2010) Asf1 can promote trimethylation of H3 K36 by Set2. Mol Cell Biol 30:1116–1129. doi:10.1128/MCB.01229-09
Liu H, Tang L (2013) Mechano-regulation of alternative splicing. Curr Genom 14:49–55. doi:10.2174/138920213804999156
Liu H, Jin T, Guan J, Zhou S (2014) Histone modifications involved in cassette exon inclusions: a quantitative and interpretable analysis. BMC Genom. doi:10.1186/1471-2164-15-1148
Lopez PJ, Séraphin B (2000) Uncoupling yeast intron recognition from transcription with recursive splicing. EMBO Rep 1:334–339. doi:10.1093/embo-reports/kvd065
Lovci MT, Ghanem D, Marr H et al (2013) Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat Struct Mol Biol 20:1434–1442. doi:10.1038/nsmb.2699
Lu JY, Sewer MB (2015) p54nrb/NONO regulates cyclic AMP-dependent glucocorticoid production by modulating phosphodiesterase mRNA splicing and degradation. Mol Cell Biol 35:1223–1237. doi:10.1128/MCB.00993-14
Luco RF, Pan Q, Tominaga K et al (2010) Regulation of alternative splicing by histone modifications. Science 327:996–1000. doi:10.1126/science.1184208
Luco RF, Allo M, Schor IE et al (2011) Epigenetics in alternative pre-mRNA splicing. Cell 144:16–26. doi:10.1016/j.cell.2010.11.056
Lykke-Andersen J, Bennett EJ (2014) Protecting the proteome: eukaryotic cotranslational quality control pathways. J Cell Biol 204:467–476. doi:10.1083/jcb.201311103
Mabon SA, Misteli T (2005) Differential recruitment of pre-mRNA splicing factors to alternatively spliced transcripts in vivo. PLoS Biol. doi:10.1371/journal.pbio.0030374
Malara A, Gruppi C, Celesti G et al (2016) Brief report: alternative splicing of extra domain A (EIIIA) of fibronectin plays a tissue-specific role in hematopoietic homeostasis. Stem Cells Dayt Ohio 34:2263–2268. doi:10.1002/stem.2381
Mallinjoud P, Villemin J-P, Mortada H et al (2014) Endothelial, epithelial, and fibroblast cells exhibit specific splicing programs independently of their tissue of origin. Genome Res 24:511–521. doi:10.1101/gr.162933.113
Marinov GK, Williams BA, McCue K et al (2014) From single-cell to cell-pool transcriptomes: stochasticity in gene expression and RNA splicing. Genome Res 24:496–510. doi:10.1101/gr.161034.113
Marquez Y, Höpfler M, Ayatollahi Z et al (2015) Unmasking alternative splicing inside protein-coding exons defines exitrons and their role in proteome plasticity. Genome Res 25:995–1007. doi:10.1101/gr.186585.114
Martinez-Contreras R, Fisette J-F, Nasim FH et al (2006) Intronic binding sites for hnRNP A/B and hnRNP F/H proteins stimulate pre-mRNA splicing. PLoS Biol. doi:10.1371/journal.pbio.0040021
Martinson HG (2011) An active role for splicing in 3′-end formation. Wiley Interdiscip Rev RNA 2:459–470. doi:10.1002/wrna.68
Matveeva E, Maiorano J, Zhang Q et al (2016) Involvement of PARP1 in the regulation of alternative splicing. Cell Discov 2:15046. doi:10.1038/celldisc.2015.46
Maunakea AK, Chepelev I, Cui K, Zhao K (2013) Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res 23:1256–1269. doi:10.1038/cr.2013.110
May GE, Olson S, McManus CJ, Graveley BR (2011) Competing RNA secondary structures are required for mutually exclusive splicing of the Dscam exon 6 cluster. RNA 17:222–229. doi:10.1261/rna.2521311
McManus CJ, Graveley BR (2011) RNA structure and the mechanisms of alternative splicing. Curr Opin Genet Dev 21:373–379. doi:10.1016/j.gde.2011.04.001
Melamud E, Moult J (2009a) Stochastic noise in splicing machinery. Nucleic Acids Res 37:4873–4886. doi:10.1093/nar/gkp471
Melamud E, Moult J (2009b) Structural implication of splicing stochastics. Nucleic Acids Res 37:4862–4872. doi:10.1093/nar/gkp444
Merkhofer EC, Hu P, Johnson TL (2014) Introduction to cotranscriptional RNA splicing. Methods Mol Biol Clifton NJ 1126:83–96. doi:10.1007/978-1-62703-980-2_6
Misra A, Green MR (2016) From polyadenylation to splicing: dual role for mRNA 3′ end formation factors. RNA Biol 13:259–264. doi:10.1080/15476286.2015.1112490
Mittendorf KF, Deatherage CL, Ohi MD, Sanders CR (2012) Tailoring of membrane proteins by alternative splicing of pre-mRNA. Biochemistry (Mosc) 51:5541–5556. doi:10.1021/bi3007065
Moore K, Hollien J (2015) Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status. Mol Biol Cell 26:2873–2884. doi:10.1091/mbc.E15-02-0074
Moore MJ, Wang Q, Kennedy CJ, Silver PA (2010) An alternative splicing network links cell cycle control to apoptosis. Cell 142:625–636. doi:10.1016/j.cell.2010.07.019
Movassat M, Crabb TL, Busch A et al (2016) Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns. RNA Biol. doi:10.1080/15476286.2016.1191727
Mozaffari-Jovin S, Wandersleben T, Santos KF et al (2014) Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans. RNA Biol 11:298–312. doi:10.4161/rna.28353
Nasim F-UH, Hutchison S, Cordeau M, Chabot B (2002) High-affinity hnRNP A1 binding sites and duplex-forming inverted repeats have similar effects on 5′ splice site selection in support of a common looping out and repression mechanism. RNA 8:1078–1089
Nickless A, Bailis JM, You Z (2017) Control of gene expression through the nonsense-mediated RNA decay pathway. Cell Biosci 7:26. doi:10.1186/s13578-017-0153-7
Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463:457–463. doi:10.1038/nature08909
Nogués G, Kadener S, Cramer P et al (2002) Transcriptional activators differ in their abilities to control alternative splicing. J Biol Chem 277:43110–43114. doi:10.1074/jbc.M208418200
Olson S, Blanchette M, Park J et al (2007) A regulator of Dscam mutually exclusive splicing fidelity. Nat Struct Mol Biol 14:1134–1140
Pan K, Lee JTH, Huang Z, Wong C-M (2015) Coupling and coordination in gene expression processes with pre-mRNA splicing. Int J Mol Sci 16:5682–5696. doi:10.3390/ijms16035682
Patrick KL, Ryan CJ, Xu J et al (2015) Genetic interaction mapping reveals a role for the SWI/SNF nucleosome remodeler in spliceosome activation in fission yeast. PLoS Genet. doi:10.1371/journal.pgen.1005074
Pervouchine DD, Khrameeva EE, Pichugina MY et al (2012) Evidence for widespread association of mammalian splicing and conserved long-range RNA structures. RNA 18:1–15. doi:10.1261/rna.029249.111
Pickrell JK, Pai AA, Gilad Y, Pritchard JK (2010) Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet. doi:10.1371/journal.pgen.1001236
Piva F, Giulietti M, Burini AB, Principato G (2012) SpliceAid 2: a database of human splicing factors expression data and RNA target motifs. Hum Mutat 33:81–85. doi:10.1002/humu.21609
Pohl M, Bortfeldt RH, Grützmann K, Schuster S (2013) Alternative splicing of mutually exclusive exons–a review. Biosystems 114:31–38. doi:10.1016/j.biosystems.2013.07.003
Pradeepa MM, Sutherland HG, Ule J et al (2012) Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS Genet. doi:10.1371/journal.pgen.1002717
Preußner M, Schreiner S, Hung L-H et al (2012) HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing. Nucleic Acids Res 40:5666–5678. doi:10.1093/nar/gks221
Raj B, Blencowe BJ (2015) Alternative splicing in the mammalian nervous system: recent insights into mechanisms and functional roles. Neuron 87:14–27. doi:10.1016/j.neuron.2015.05.004
Ringrose L (2010) How do RNA sequence, DNA sequence, and chromatin properties regulate splicing? F1000 Biol Rep. doi:10.3410/B2-74
Romano M, Marcucci R, Baralle FE (2001) Splicing of constitutive upstream introns is essential for the recognition of intra-exonic suboptimal splice sites in the thrombopoietin gene. Nucleic Acids Res 29:886–894
Romano M, Buratti E, Baralle D (2013) Role of pseudoexons and pseudointrons in human cancer. Int J Cell Biol. doi:10.1155/2013/810572
Rossbach O, Hung L-H, Schreiner S et al (2009) Auto- and cross-regulation of the hnRNP L proteins by alternative splicing. Mol Cell Biol 29:1442–1451. doi:10.1128/MCB.01689-08
Rossbach O, Hung L-H, Khrameeva E et al (2014) Crosslinking-immunoprecipitation (iCLIP) analysis reveals global regulatory roles of hnRNP L. RNA Biol 11:146–155. doi:10.4161/rna.27991
Roy CK, Olson S, Graveley BR et al (2015) Assessing long-distance RNA sequence connectivity via RNA-templated DNA–DNA ligation. eLife. doi:10.7554/eLife.03700
Rueter SM, Dawson TR, Emeson RB (1999) Regulation of alternative splicing by RNA editing. Nature 399:75–80. doi:10.1038/19992
Russcher H, Dalm VASH, de Jong FH et al (2007) Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene. J Mol Endocrinol 38:91–98. doi:10.1677/jme.1.02117
Sahoo A, Im S-H (2010) Interleukin and interleukin receptor diversity: role of alternative splicing. Int Rev Immunol 29:77–109. doi:10.3109/08830180903349651
Saldi T, Cortazar MA, Sheridan RM, Bentley DL (2016) Coupling of RNA polymerase II transcription elongation with pre-mRNA splicing. J Mol Biol 428:2623–2635. doi:10.1016/j.jmb.2016.04.017
Sanidas I, Polytarchou C, Hatziapostolou M et al (2014) Phosphoproteomics screen reveals Akt isoform-specific signals linking RNA processing to lung cancer. Mol Cell 53:577–590. doi:10.1016/j.molcel.2013.12.018
Schaal TD, Maniatis T (1999) Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences. Mol Cell Biol 19:1705–1719
Schor IE, Llères D, Risso GJ et al (2012) Perturbation of chromatin structure globally affects localization and recruitment of splicing factors. PLoS One. doi:10.1371/journal.pone.0048084
Scott LM, Rebel VI (2013) Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors. J Natl Cancer Inst 105:1540–1549. doi:10.1093/jnci/djt257
Semlow DR, Staley JP (2012) Staying on message: ensuring fidelity in pre-mRNA splicing. Trends Biochem Sci 37:263–273. doi:10.1016/j.tibs.2012.04.001
Shalek AK, Satija R, Adiconis X et al (2013) Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498:236–240. doi:10.1038/nature12172
Sharon D, Tilgner H, Grubert F, Snyder M (2013) A single-molecule long-read survey of the human transcriptome. Nat Biotechnol 31:1009–1014. doi:10.1038/nbt.2705
Shepard PJ, Hertel KJ (2008) Conserved RNA secondary structures promote alternative splicing. RNA 14:1463–1469. doi:10.1261/rna.1069408
Shukla S, Kavak E, Gregory M et al (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479:74–79. doi:10.1038/nature10442
Sibley CR, Emmett W, Blazquez L et al (2015) Recursive splicing in long vertebrate genes. Nature 521:371–375. doi:10.1038/nature14466
Singh NN, Seo J, Rahn SJ, Singh RN (2012) A multi-exon-skipping detection assay reveals surprising diversity of splice isoforms of spinal muscular atrophy genes. PLoS One. doi:10.1371/journal.pone.0049595
Singh NN, Lee BM, Singh RN (2015) Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions. Ann N Y Acad Sci 1341:176–187. doi:10.1111/nyas.12727
Solomon O, Oren S, Safran M et al (2013) Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR). RNA 19:591–604. doi:10.1261/rna.038042.112
Sorek R, Shamir R, Ast G (2004) How prevalent is functional alternative splicing in the human genome? Trends Genet TIG 20:68–71. doi:10.1016/j.tig.2003.12.004
Spies N, Nielsen CB, Padgett RA, Burge CB (2009) Biased chromatin signatures around polyadenylation sites and exons. Mol Cell 36:245–254. doi:10.1016/j.molcel.2009.10.008
Stepankiw N, Raghavan M, Fogarty EA et al (2015) Widespread alternative and aberrant splicing revealed by lariat sequencing. Nucleic Acids Res 43:8488–8501. doi:10.1093/nar/gkv763
Suyama M (2013) Mechanistic insights into mutually exclusive splicing in dynamin 1. Bioinformatics 29:2084–2087. doi:10.1093/bioinformatics/btt368
Szafranski K, Fritsch C, Schumann F et al (2014) Physiological state co-regulates thousands of mammalian mRNA splicing events at tandem splice sites and alternative exons. Nucleic Acids Res 42:8895–8904. doi:10.1093/nar/gku532
Tang ZZ, Zheng S, Nikolic J, Black DL (2009) Developmental control of CaV1.2 L-type calcium channel splicing by Fox proteins. Mol Cell Biol 29:4757–4765. doi:10.1128/MCB.00608-09
Tang ZZ, Sharma S, Zheng S et al (2011) Regulation of the mutually exclusive exons 8a and 8 in the CaV1.2 calcium channel transcript by polypyrimidine tract-binding protein. J Biol Chem 286:10007–10016. doi:10.1074/jbc.M110.208116
Tasnim M, Ma S, Yang E-W et al (2015) Accurate inference of isoforms from multiple sample RNA-Seq data. BMC Genom 16(Suppl 2):S15. doi:10.1186/1471-2164-16-S2-S15
Taube JR, Sperle K, Banser L et al (2014) PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing. Hum Mol Genet 23:5464–5478. doi:10.1093/hmg/ddu271
Teplova M, Song J, Gaw HY et al (2010) Structural insights into RNA recognition by the alternate-splicing regulator CUG binding protein 1. Struct Engl 18:1364–1377. doi:10.1016/j.str.2010.06.018
Tilgner H, Knowles DG, Johnson R et al (2012) 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. doi:10.1101/gr.134445.111
Tilgner H, Grubert F, Sharon D, Snyder MP (2014) Defining a personal, allele-specific, and single-molecule long-read transcriptome. Proc Natl Acad Sci USA 111:9869–9874. doi:10.1073/pnas.1400447111
Tilgner H, Jahanbani F, Blauwkamp T et al (2015) Comprehensive transcriptome analysis using synthetic long-read sequencing reveals molecular co-association of distant splicing events. Nat Biotechnol 33:736–742. doi:10.1038/nbt.3242
Trapnell C, Williams BA, Pertea G et al (2010) Transcript assembly and abundance estimation from RNA-Seq reveals thousands of new transcripts and switching among isoforms. Nat Biotechnol 28:511–515. doi:10.1038/nbt.1621
Tress ML, Abascal F, Valencia A (2016) Alternative splicing may not be the key to proteome complexity. Trends Biochem Sci. doi:10.1016/j.tibs.2016.08.008
Tripathi V, Ellis JD, Shen Z et al (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938. doi:10.1016/j.molcel.2010.08.011
Uemura A, Oku M, Mori K, Yoshida H (2009) Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein response. J Cell Sci 122:2877–2886. doi:10.1242/jcs.040584
Volanakis A, Passoni M, Hector RD et al (2013) Spliceosome-mediated decay (SMD) regulates expression of nonintronic genes in budding yeast. Genes Dev 27:2025–2038. doi:10.1101/gad.221960.113
Waks Z, Klein AM, Silver PA (2011) Cell-to-cell variability of alternative RNA splicing. Mol Syst Biol 7:506. doi:10.1038/msb.2011.32
Wang ET, Sandberg R, Luo S et al (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476. doi:10.1038/nature07509
Wang X, Li G, Yang Y et al (2012a) An RNA architectural locus control region involved in Dscam mutually exclusive splicing. Nat Commun 3:1255. doi:10.1038/ncomms2269
Wang Y, Ma M, Xiao X, Wang Z (2012b) Intronic splicing enhancers, cognate splicing factors and context dependent regulation rules. Nat Struct Mol Biol 19:1044–1052. doi:10.1038/nsmb.2377
Wang Y, Xiao X, Zhang J et al (2013) A complex network of factors with overlapping affinities repress splicing through intronic elements. Nat Struct Mol Biol 20:36–45. doi:10.1038/nsmb.2459
Warf MB, Berglund JA (2010) The role of RNA structure in regulating pre-mRNA splicing. Trends Biochem Sci 35:169–178. doi:10.1016/j.tibs.2009.10.004
Warf MB, Diegel JV, von Hippel PH, Berglund JA (2009) The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proc Natl Acad Sci USA 106:9203–9208. doi:10.1073/pnas.0900342106
Warns JA, Davie JR, Dhasarathy A (2016) Connecting the dots: chromatin and alternative splicing in EMT. Biochem Cell Biol Biochim Biol Cell 94:12–25. doi:10.1139/bcb-2015-0053
Weischenfeldt J, Waage J, Tian G et al (2012) Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns. Genome Biol 13:R35. doi:10.1186/gb-2012-13-5-r35
Welch JD, Hu Y, Prins JF (2016) Robust detection of alternative splicing in a population of single cells. Nucleic Acids Res. doi:10.1093/nar/gkv1525
Wollerton MC, Gooding C, Wagner EJ et al (2004) Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay. Mol Cell 13:91–100
Wong TN, Pan T (2009) RNA folding during transcription: protocols and studies. Methods Enzymol 468:167–193. doi:10.1016/S0076-6879(09)68009-5
Wong JJ-L, Ritchie W, Ebner OA et al (2013) Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154:583–595. doi:10.1016/j.cell.2013.06.052
Wu L, Zhang X, Zhao Z et al (2015) Full-length single-cell RNA-seq applied to a viral human cancer: applications to HPV expression and splicing analysis in HeLa S3 cells. GigaScience 4:51. doi:10.1186/s13742-015-0091-4
Xin D, Hu L, Kong X (2008) Alternative promoters influence alternative splicing at the genomic level. PLoS One. doi:10.1371/journal.pone.0002377
Xing Y, Yu T, Wu YN et al (2006) An expectation-maximization algorithm for probabilistic reconstructions of full-length isoforms from splice graphs. Nucleic Acids Res 34:3150–3160. doi:10.1093/nar/gkl396
Yan Q, Weyn-Vanhentenryck SM, Wu J et al (2015) Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Proc Natl Acad Sci USA 112:3445–3450. doi:10.1073/pnas.1502849112
Yang L, Lin C, Liu W et al (2011a) ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147:773–788. doi:10.1016/j.cell.2011.08.054
Yang Y, Zhan L, Zhang W et al (2011b) RNA secondary structure in mutually exclusive splicing. Nat Struct Mol Biol 18:159–168. doi:10.1038/nsmb.1959
Yap K, Makeyev EV (2013) Regulation of gene expression in mammalian nervous system through alternative pre-mRNA splicing coupled with RNA quality control mechanisms. Mol Cell Neurosci 56:420–428. doi:10.1016/j.mcn.2013.01.003
Yap K, Makeyev EV (2016) Functional impact of splice isoform diversity in individual cells. Biochem Soc Trans 44:1079–1085. doi:10.1042/BST20160103
Yap K, Lim ZQ, Khandelia P et al (2012) Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev 26:1209–1223. doi:10.1101/gad.188037.112
Yearim A, Gelfman S, Shayevitch R et al (2015) HP1 is involved in regulating the global impact of DNA methylation on alternative splicing. Cell Rep 10:1122–1134. doi:10.1016/j.celrep.2015.01.038
Yeo G, Holste D, Kreiman G, Burge CB (2004) Variation in alternative splicing across human tissues. Genome Biol 5:R74. doi:10.1186/gb-2004-5-10-r74
Yeo GW, Nostrand ELV, Liang TY (2007) Discovery and analysis of evolutionarily conserved intronic splicing regulatory elements. PLoS Genet. doi:10.1371/journal.pgen.0030085
Yu Y, Reed R (2015) FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP. Proc Natl Acad Sci USA 112:8608–8613. doi:10.1073/pnas.1506282112
Yue Y, Yang Y, Dai L et al (2016) Long-range RNA pairings contribute to mutually exclusive splicing. RNA N Y N 22:96–110. doi:10.1261/rna.053314.115
Zamft B, Bintu L, Ishibashi T, Bustamante C (2012) Nascent RNA structure modulates the transcriptional dynamics of RNA polymerases. Proc Natl Acad Sci USA 109:8948–8953. doi:10.1073/pnas.1205063109
Zhang Z, Xin D, Wang P et al (2009) Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay. BMC Biol 7:23. doi:10.1186/1741-7007-7-23
Zhang J, Kuo CJ, Chen L (2011) GC content around splice sites affects splicing through pre-mRNA secondary structures. BMC Genom 12:90. doi:10.1186/1471-2164-12-90
Zhang J, Lieu YK, Ali AM et al (2015) Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities. Proc Natl Acad Sci USA 112:E4726–E4734. doi:10.1073/pnas.1514105112
Zhou H-L, Hinman MN, Barron VA et al (2011) Hu proteins regulate alternative splicing by inducing localized histone hyperacetylation in an RNA-dependent manner. Proc Natl Acad Sci USA 108:E627–E635. doi:10.1073/pnas.1103344108
Zhou H-L, Luo G, Wise JA, Lou H (2014) Regulation of alternative splicing by local histone modifications: potential roles for RNA-guided mechanisms. Nucleic Acids Res 42:701–713. doi:10.1093/nar/gkt875
Zhu J, Shendure J, Mitra RD, Church GM (2003) Single molecule profiling of alternative pre-mRNA splicing. Science 301:836–838. doi:10.1126/science.1085792
Zhu S, Wang G, Liu B, Wang Y (2013) Modeling exon expression using histone modifications. PLoS One. doi:10.1371/journal.pone.0067448
Zubović L, Baralle M, Baralle FE (2012) Mutually exclusive splicing regulates the Nav 1.6 sodium channel function through a combinatorial mechanism that involves three distinct splicing regulatory elements and their ligands. Nucleic Acids Res 40:6255–6269. doi:10.1093/nar/gks249
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We thank Dr. Alexandra Radzisheuskaya (Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark) for critical reading of the manuscript.
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This work was supported in part by the Ministry of Education of the Republic of Belarus, grant #3.08.3 (947/54).
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Ramanouskaya, T.V., Grinev, V.V. The determinants of alternative RNA splicing in human cells. Mol Genet Genomics 292, 1175–1195 (2017). https://doi.org/10.1007/s00438-017-1350-0
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DOI: https://doi.org/10.1007/s00438-017-1350-0