Цитологія і генетика 2023, том 57, № 5, 33-57
Cytology and Genetics 2023, том 57, № 5, 413–431, doi: https://www.doi.org/https://doi.org/10.3103/S0095452723050055

Механізми інтрон-опосередкованого посилення експресії: ласкаво просимо до готелю Каліфорнія

Пидюра М.О., Блюм Я.Б.

  1. Інститут харчової біотехнології та геноміки НАН України, вул. Байди­Вишневецького (Осиповського), 2A, 04123, Київ, Україна
  2. АТ «Фармак», вул. Кирилівська, 63, 04080, Київ, Україна

Явище позитивного впливу інтронів на експресію гена, в якому вони знаходяться, що отримало назву інтрон-опосередкованого посилення (IME), характерне для широкого кола різноманітних організмів, включаючи нематод, комах, ссавців, грибів та рослин, відбувається завдяки досі невизначеному фундаментальному механізму. IME інтрони вже тривалий час використовуються, зокрема, у біотехнології рослин. Розуміння механізмів даного явища дозволить передбачати та легко генерувати стимулюючі інтрони із заданими властивостями та створювати дуже вигідні фенотипи. Це також увімкне зелене світло для використання IME у генній терапії та для покращення виробництва фармацевтичних білків. У огляді проаналізовано раніше запропоновані моделі механізмів функціонування IME і виділено фактори, які можуть напряму або опосередковано визначати IME за різних умов і на різних рівнях експресії генів, таких як експериментальні методи дослідження ІМЕ, регуляторні РНК, властивості послідовності, позиція та орієнтація інтронів, фактори на рівні ДНК, транскрипції, сплайсингу, мРНК, трансляції, гени, у яких виявляється IME, тканинна специфічність, репресія та співвідношення за значенням між деякими з факторів. Оскільки не існує єдиного механізму IME, і ефект може відрізнятись у різних видів, при моделюванні цього процесу слід порівнювати між собою лише випадки IME, які впливають на експресію на одному і тому ж самому рівні, враховуючи експериментальні умови. Виділення біологічних факторів, які можуть визначати IME, та співвідношень між ними допоможе в подальшому створити відповідний набір даних, зручний для машинного навчання, та спробувати розгадати таємницю феномену IME за допомогою машинного навчання.

Ключові слова: Інтрон, експресія гена, інтрон-опосе-редковане посилення, ІМЕ, фактори ІМЕ, регуляція експресії, машинне начання

Цитологія і генетика
2023, том 57, № 5, 33-57

Current Issue
Cytology and Genetics
2023, том 57, № 5, 413–431,
doi: https://doi.org/10.3103/S0095452723050055

Повний текст та додаткові матеріали

Цитована література

Agarwal, N.Yu. and Ansari, A., Enhancement of transcription by a splicing-competent intron is dependent on promoter directionality, PLoS Genet., 2016, vol. 12, no. 5, p. e1006047. https://doi.org/10.1371/journal.pgen.1006047

Akua, T. and Shaul, O., The Arabidopsis thaliana MHX gene includes an intronic element that boosts translation when localized in a 5' UTR intron, J. Exp. Bot., 2013, vol. 64, no. 14, pp. 4255–4270. https://doi.org/10.1093/jxb/ert235

Akua, T., Berezin, I., and Shaul, O., The leader intron of AtMHX can elicit, in the absence of splicing, low-level intron-mediated enhancement that depends on the internal intron sequence, BMC Plant Biol., 2010, vol. 10, p. 93. https://doi.org/10.1186/1471-2229-10-93

Al-Husini, N., Medler, S., and Ansari, A., Crosstalk of promoter and terminator during RNA polymerase II transcription cycle, Biochim. Biophys. Acta, Gene Regul. Mech., 2020, vol. 1863, no. 12, p. 194657. https://doi.org/10.1016/j.bbagrm.2020.194657

Alipanahi, B., Delong, A., Weirauch, M.T., et al., Predicting the sequence specificities of DNA- and RNA-binding proteins by deep learning, Nat. Biotechnol., 2015, vol. 33, no. 8, pp. 831–838. https://doi.org/10.1038/nbt.3300

Auslander, N., Gussow, A.B., and Koonin, E.V., Incorporating machine learning into established bioinformatics frameworks, Int. J. Mol. Sci., 2021, vol. 22, no. 6, p. 2903. https://doi.org/10.3390/ijms22062903

Baier, T., Jacobebbinghaus, N., Einhaus, A., et al., Introns mediate post-transcriptional enhancement of nuclear gene expression in the green microalga Chlamydomonas reinhardtii, PLoS Genet., 2020, vol. 16, no. 7, p. e1008944. https://doi.org/10.1371/journal.pgen.1008944

Barshai, M., Tripto, E., and Orenstein, Y., Identifying regulatory elements via deep learning, Annu. Rev. Biomed. Data Sci., 2020, vol. 3, pp. 315–338. https://doi.org/10.1146/annurev-biodatasci-022020-021940

Basso, M.F., Arraes, F.B.M., Grossi-de-Sa, M., et al., Insights into genetic and molecular elements for transgenic crop development, Front. Plant Sci., 2020, vol. 11, p. 509. https://doi.org/10.3389/fpls.2020.00509

Bhatti, G.K., Khullar, N., Sidhu, I.S., et al., Emerging role of non-coding RNA in health and disease, Metab. Brain Dis., 2021, vol. 36, no. 6, pp. 1119–1134. https://doi.org/10.1007/s11011-021-00739-y

Bieberstein, N.I., Carrillo Oesterreich, F., Straube, K., et al., First exon length controls active chromatin signatures and transcription, Cell Rep., 2012, vol. 2, no. 1, pp. 62–68. https://doi.org/10.1016/j.celrep.2012.05.019

Boehm, V. and Gehring, N.H., Exon junction complexes: supervising the gene expression assembly line, Trends Genet., 2016, vol. 32, no. 11, pp. 724–735. https://doi.org/10.1016/j.tig.2016.09.003

Bogard, B., Francastel, C., and Hubé, F., Multiple information carried by RNAs: total eclipse or a light at the end of the tunnel?, RNA Biol., 2020, vol. 17, no. 12, pp. 1707–1720. https://doi.org/10.1080/15476286.2020.1783868

Bourdon, V., Harvey, A., and Lonsdale, D.M., Introns and their positions affect the translational activity of mRNA in plant cells, EMBO Rep., 2001, vol. 2, no. 5, pp. 394–398. https://doi.org/10.1093/embo-reports/kve090

Bradnam, K.R. and Korf, I., Longer first introns are a general property of eukaryotic gene structure, PLoS One, 2008, vol. 3, no. 8, p. e3093. https://doi.org/10.1371/journal.pone.0003093

Callis, J., Fromm, M., and Walbot, V., Introns increase gene expression in cultured maize cells, Genes Dev., 1987, vol. 1, no. 10, pp. 1183–1200. https://doi.org/10.1101/gad.1.10.1183

Casas-Mollano, J.A., Lao, N.T., and Kavanagh, T.A., Intron-regulated expression of SUVH3, an Arabidopsis Su(var)3-9 homologue, J. Exp. Bot., 2006, vol. 57, no. 12, pp. 3301–3311. https://doi.org/10.1093/jxb/erl093

Chaubet-Gigot, N., Kapros, T., Flenet, M., et al., Tissue-dependent enhancement of transgene expression by introns of replacement histone H3 genes of Arabidopsis, Plant Mol Biol., 2001, vol. 45, no. 1, pp. 17–30. https://doi.org/10.1023/a:1006487023926

Chaudhary, S., Khokhar, W., Jabre, I., et al., Alternative splicing and protein diversity: plants versus animals, Front. Plant Sci., 2019, vol. 10, p. 708. https://doi.org/10.3389/fpls.2019.00708

Chicco, D., Ten quick tips for machine learning in computational biology, BioData Min., 2017, vol. 10, p. 35. https://doi.org/10.1186/s13040-017-0155-3

Chorev, M. and Carmel, L., The function of introns, Front. Genet., 2012, vol. 3, p. 55. https://doi.org/10.3389/fgene.2012.00055

Chung, B.Y., Simons, C., Firth, A.E., et al., Effect of 5′UTR introns on gene expression in Arabidopsis thaliana, BMC Genomics, 2006, vol. 7, p. 120. https://doi.org/10.1186/1471-2164-7-120

Clancy, M. and Hannah, L.C., Splicing of the maize Sh1 first intron is essential for enhancement of gene expression, and a T-rich motif increases expression without affecting splicing, Plant Physiol., 2002, vol. 130, no. 2, pp. 918–929. https://doi.org/10.1104/pp.008235

Clancy, M., Vasil, V., Hannah, C.L., et al., Maize Shrunken-1 intron and exon regions increase gene expression in maize protoplasts, Plant Sci., 2002, vol. 98, pp. 151–161. https://doi.org/10.1016/0168-9452(94)90005-1

Curi, G.C., Chan, R.L., and Gonzalez, D.H., The leader intron of Arabidopsis thaliana genes encoding cytochrome c oxidase subunit 5c promotes high-level expression by increasing transcript abundance and translation efficiency, J. Exp. Bot., 2005, vol. 56, pp. 419, pp. 2563–2571. https://doi.org/10.1093/jxb/eri250

Custódio, N. and Carmo-Fonseca, M., Co-transcriptional splicing and the CTD code, Crit. Rev. Biochem. Mol. B-iol., 2016, vol. 51, no. 5, pp. 395–411. https://doi.org/10.1080/10409238.2016.1230086

Damgaard, C.K., Kahns, S., Lykke-Andersen, S., et al., A 5′ splice site enhances the recruitment of basal transcription initiation factors in vivo, Mol. Cell., 2008, vol. 29, no. 2, pp. 271–278. https://doi.org/10.1016/j.molcel.2007.11.035

David-Assael, O., Berezin, I., Shoshani-Knaani, N., et al., AtMHX is an auxin and ABA-regulated transporter whose expression pattern suggests a role in metal homeostasis in tissues with photosynthetic potential, Funct. Plant Biol., 2006, vol. 33, no. 7, pp. 661–672. https://doi.org/10.1071/FP05295

Dean, C., Favreau, M., Bond-Nutter, D., et al., Sequences downstream of translation start regulate quantitative expression of two petunia rbcS genes, Plant Cell, 1989, vol. 1, no. 2, pp. 201–208. https://doi.org/10.1105/tpc.1.2.201

Depicker, A. and Montagu, M.V., Post-transcriptional gene silencing in plants, Curr. Opin. Cell Biol., 1997, vol. 9, no. 3, pp. 373–382. https://doi.org/10.1016/s0955-0674(97)80010-5

Donath, M., Mendel, R., Cerff, R., et al., Intron-dependent transient expression of the maize GapA1 gene, Plant Mol. Biol., 1995, vol. 28, no. 4, pp. 667–676. https://doi.org/10.1007/BF00021192

Dwyer, K., Agarwal, N., Gega, A., et al., Proximity to the promoter and terminator regions regulates the transcription enhancement potential of an intron, Front. Mol. Biosci., 2021a, vol. 8, p. 712639. https://doi.org/10.3389/fmolb.2021.712639

Dwyer, K., Agarwal, N., Pile, L., et al., Gene architecture facilitates intron-mediated enhancement of transcription, Front. Mol. Biosci., 2021b, vol. 8, p. 669004. https://doi.org/10.3389/fmolb.2021.669004

Eamens, A., Wang, M.B., Smith, N.A., et al., RNA silencing in plants: yesterday, today, and tomorrow, Plant Physiol., 2008, vol. 147, no. 2, pp. 456–468. https://doi.org/10.1104/pp.108.117275

Emami, S., Arumainayagam, D., Korf, I., et al., The effects of a stimulating intron on the expression of heterologous genes in Arabidopsis thaliana, Plant Biotechnol. J., 2013, vol. 11, no. 5, pp. 555–563. https://doi.org/10.1111/pbi.12043

Eraslan, G., Avsec, Ž., Gagneur, J., et al., Deep learning: new computational modelling techniques for genomics, Nat. Rev. Genet., 2019, vol. 20, no. 7, pp. 389–403. https://doi.org/10.1038/s41576-019-0122-6

Fagard, M. and Vaucheret, H., (Trans)gene silencing in plants: how many mechanisms?, Annu. Rev. Plant Physiol. Plant Mol. Biol., 2000, vol. 51, pp. 167–194. https://doi.org/10.1104/pp.108.117275

Fiume, E., Christou, P., Gianì, S., et al., Introns are key regulatory elements of rice tubulin expression, Planta, 2004, vol. 218, no. 5, pp. 693–703. https://doi.org/10.1007/s00425-003-1150-0

Furger, A., O’Sullivan, J.M., Binnie, A., et al., Promoter proximal splice sites enhance transcription, Genes Dev., 2002, vol. 16, no. 21, pp. 2792–2799. https://doi.org/10.1101/gad.983602

Gallegos, J.E. and Rose, A.B., The enduring mystery of intron-mediated enhancement, Plant Sci., 2015, vol. 237, pp. 8–15. https://doi.org/10.1016/j.plantsci.2015.04.017

Gallegos, J.E. and Rose, A.B., Intron DNA Sequences can be more important than the proximal promoter in determining the site of transcript initiation, Plant Cell., 2017, vol. 29, no. 4, pp. 843–853. https://doi.org/10.1105/tpc.17.00020

Gallegos, J.E. and Rose, A.B., An intron-derived motif strongly increases gene expression from transcribed sequences through a splicing independent mechanism in Arabidopsis thaliana, Sci. Rep., 2019, vol. 9, no. 1, p. 13777. https://doi.org/10.1038/s41598-019-50389-5

Gallois, J.L., Drouaud, J., Lécureuil, A., et al., Functional characterization of the plant ubiquitin regulatory X (UBX) domain-containing protein AtPUX7 in Arabidopsis thaliana, Gene, 2013, vol. 526, no. 2, pp. 299–308. https://doi.org/10.1016/j.gene.2013.05.056

Gianì, S., Altana, A., Campanoni, P., et al., In transgenic rice, α- and β-tubulin regulatory sequences control GUS amount and distribution through intron mediated enhancement and intron dependent spatial expression, Transgenic Res., 2009, vol. 18, no. 2, pp. 151–162. https://doi.org/10.1007/s11248-008-9202-7

Gidekel, M., Jimenez, B., and Herrera-Estrella, L., The first intron of the Arabidopsis thaliana gene coding for elongation factor 1β contains an enhancer-like element, Gene, 1996, vol. 170, no. 2, pp. 201–206. https://doi.org/10.1016/0378-1119(95)00837-3

Gromadzka, A.M., Steckelberg, A.L., Singh, K.K., et al., A short conserved motif in ALYREF directs cap- and EJC-dependent assembly of export complexes on spliced mRNAs, Nucleic Acids Res., 2016, vol. 44, no. 5, pp. 2348–2361. https://doi.org/10.1093/nar/gkw009

Hu, X., Fernie, A.R., and Yan, J., Deep learning in regulatory genomics: from identification to design, Curr. Opin. Biotechnol., 2023, vol. 79, p. 102887. https://doi.org/10.1016/j.copbio.2022.102887

Jefferson, R.A., Kavanagh, T.A., and Bevan, M.W., GUS fusions: beta-glucuronidase as a sensitive and versatile gene fusion marker in higher plants, EMBO J., 1987, vol. 6, no. 13, pp. 3901–3907. https://doi.org/10.1002/j.1460-2075.1987.tb02730.x

Jeon, J.S., Lee, S., Jung, K.H., et al., Tissue-preferential expression of a rice α-tubulin gene, OsTubA1, mediated by the first intron, Plant Physiol., 2000, vol. 123, no. 3, pp. 1005–1014. https://doi.org/10.1104/pp.123.3.1005

Jeong, Y.M., Mun, J.H., Lee, I., et al., Distinct roles of the first introns on the expression of Arabidopsis profilin gene family members, Plant Physiol., 2006, vol. 140, no. 1, pp. 196–209. https://doi.org/10.1104/pp.105.071316

Jeong, Y.M., Mun, J.H., Kim, H., et al., An upstream region in the first intron of petunia actin-depolymerizing factor 1 affects tissue-specific expression in transgenic Arabidopsis (Arabidopsis thaliana), Plant J., 2007, vol. 50, no. 2, pp. 230–239. https://doi.org/10.1111/j.1365-313X.2007.03053.x

Jo, B.S. and Choi, S.S., Introns: the functional benefits of introns in genomes, Genomics Inf., 2015, vol. 13, no. 4, pp. 112–118. https://doi.org/10.5808/GI.2015.13.4.112

Jo, S.S. and Choi, S.S., Enrichment of rare alleles within epigenetic chromatin marks in the first intron, Genomics Inf., 2019a, vol. 17, no. 1, p. e9. https://doi.org/10.5808/GI.2019.17.1.e9

Jo, S.S. and Choi, S.S., Analysis of the functional relevance of epigenetic chromatin marks in the first intron associated with specific gene expression patterns, Genome Bio-l. Evol., 2019b, vol. 11, no. 3, pp. 786–797. https://doi.org/10.1093/gbe/evz033

Karthikeyan, A.S., Ballachanda, D.N., and Raghothama, K.G. Promoter deletion analysis elucidates the role of cis elements and 5′UTR intron in spatiotemporal regulation of AtPht1;4 expression in Arabidopsis, Physiol. Plant., 2009, vol. 136, no. 1, pp. 10–18. https://doi.org/10.1111/j.1399-3054.2009.01207.x

Kertész, S., Kerényi, Z., Mérai, Z., et al., Both introns and long 3′-UTRs operate as cis-acting elements to trigger nonsense-mediated decay in plants, Nucleic Acids Res., 2006, vol. 34, no. 21, pp. 6147–6157. https://doi.org/10.1093/nar/gkl737

Kim, M.J., Kim, H., Shin, J.S., et al., Seed-specific expression of sesame microsomal oleic acid desaturase is controlled by combinatorial properties between negative cis-regulatory elements in the SeFAD2 promoter and enhancers in the 5'-UTR intron, Mol. Genet. Genomics, 2006, vol. 276, no. 4, pp. 351–368. https://doi.org/10.1007/s00438-006-0148-2

Kim, S., Kim, H., Fong, N., et al., Pre-mRNA splicing is a determinant of histone H3K36 methylation, Proc. Natl. Acad. Sci. U. S. A., 2011, vol. 108, no. 33, pp. 13564–13569. https://doi.org/10.1073/pnas.1109475108

Kooter, J.M., Matzke, M.A., and Meyer, P., Listening to the silent genes: transgene silencing, gene regulation and pathogen control, Trends Plant Sci., 1999, vol. 4, no. 9, pp. 340–347. https://doi.org/10.1016/s1360-1385(99)01467-3

Korf, I.F. and Rose, A.B., Applying word-based algorithms: The IMEter, Methods Mol. Biol., 2009, vol. 553, pp. 287–301. https://doi.org/10.1007/978-1-60327-563-7_14

Laxa, M., Intron-mediated enhancement: a tool for heterologous gene expression in plants?, Front. Plant Sci., 2017, vol. 7, p. 1977. https://doi.org/10.3389/fpls.2016.01977

Laxa, M., Müller, K., Lange, N., et al., The 5'UTR intron of Arabidopsis GGT1 aminotransferase enhances promoter activity by recruiting RNA polymerase II, Plant Physiol., 2016, vol. 172, no. 1, pp. 313–327. https://doi.org/10.1104/pp.16.00881

Le Hir, H., Gatfield, D., Izaurralde, E., et al., The exonexon junction complex provides a binding platform for factors involved in mRNA export and nonsense mediated mRNA decay, EMBO J., 2001, vol. 20, no. 17, pp. 4987–4997. https://doi.org/10.1093/emboj/20.17.4987

Le Hir, H., Nott, A., and Moore, M.J., How introns influence and enhance eukaryotic gene expression, Trends Biochem. Sci., 2003, vol. 28, no. 4, pp. 215–220. https://doi.org/10.1016/S0968-0004(03)00052-5

Le Hir, H., Saulière, J., and Wang, Z., The exon junction complex as a node of post-transcriptional networks, Nat. Rev. Mol. Cell Biol., 2016, vol. 17, no. 1, pp. 41–54. https://doi.org/10.1038/nrm.2015.7

Liao, L., Ning, G., Liu, C., et al., The intron from the 5'-UTR of the FBP11 gene in petunia displays promoter- and enhancer-like functions, Sci Hortic., 2013, vol. 154, pp. 96–101. https://doi.org/10.1016/j.scienta.2013.02.009

Lim, C.S.T., Wardell, S.J., Kleffmann, T., et al., The exon-intron gene structure upstream of the initiation codon predicts translation efficiency, Nucleic Acids Res., 2018, vol. 46, no. 9, pp. 4575–4591. https://doi.org/10.1093/nar/gky282

Lu, S. and Cullen, B.R., Analysis of the stimulatory effect of splicing on mRNA production and utilization in mammalian cells, RNA, 2003, vol. 9, no. 5, pp. 618–630. https://doi.org/10.1261/rna.5260303

Lu, J., Sivamani, E., Li, X., et al., Activity of the 5' regulatory regions of the rice polyubiquitin rubi3 gene in transgenic rice plants as analyzed by both GUS and GFP reporter genes, Plant Cell Rep., 2008, vol. 27, no. 10, pp. 1587–1600. https://doi.org/10.1007/s00299-008-0577-y

Luehrsen, K.R. and Walbot, V., Intron enhancement of gene expression and the splicing efficiency of introns in maize cells, Mol. Gen. Genet., 1991, vol. 225, no. 1, pp. 81–93. https://doi.org/10.1007/BF00282645

Maas, C., Laufs, J., Grant, S., et al., The combination of a novel stimulatory element in the first exon of the maize Shrunken-1 gene with the following intron 1 enhances reporter gene expression up to 1000-fold, Plant Mol. Bi-ol., 1991, vol. 16, no. 2, pp. 199–207. https://doi.org/10.1007/BF00020552

Mascarenhas, D., Mettler, I.J., Pierce, D.A., et al., Intron-mediated enhancement of heterologous gene expression in maize, Plant Mol. Biol., 1990, vol. 15, no. 6, pp. 913–920. https://doi.org/10.1007/BF00039430

McElroy, D., Zhang, W., Cao, J., et al., Isolation of an efficient actin promoter for use in rice transformation, Plant Cell, 1990, vol. 2 no. 2, pp. 163–171. https://doi.org/10.1105/tpc.2.2.163

Meagher, R.B., McKinney, E.C., and Vitale, A.V., The evolution of new structures: clues from plant cytoskeletal genes, Trends Genet., 1999, vol. 15, no. 7, pp. 278–284. https://doi.org/10.1016/s0168-9525(99)01759-x

Moabbi, A.M., Agarwal, N., El Kaderi, B., et al., Role for gene looping in intron-mediated enhancement of transcription, Proc. Natl. Acad. Sci. U. S. A., 2012, vol. 109, no. 22, pp. 8505–8510. https://doi.org/10.1073/pnas.1112400109

Morello, L. and Breviario, D., Plant spliceosomal introns: not only cut and paste, Curr. Genomics, 2008, vol. 9, no. 4, pp. 227–238. https://doi.org/10.2174/138920208784533629

Morello, L., Bardini, M., Sala, F., et al., A long leader intron of the Ostub16 rice β-tubulin gene is required for high-level gene expression and can autonomously promote transcription both in vivo and in vitro, Plant J., 2002, vol. 29, no. 1, pp. 33–44. https://doi.org/10.1046/j.0960-7412.2001.01192.x

Morello, L., Bardini, M., Cricrì, M., et al., Functional analysis of DNA sequences controlling the expression of the rice OsCDPK2 gene, Planta, 2006, vol. 223, no. 3, pp. 479–491. https://doi.org/10.1007/s00425-005-0105-z

Morello, L., Gianì, S., Troina, F., et al., Testing the IMEter on rice introns and other aspects of intron-mediated enhancement of gene expression, J. Exp. Bot., 2011, vol. 62, no. 2, pp. 533–544. https://doi.org/10.1093/jxb/erq273

Morita, S., Tsukamoto, S., Sakamoto, A., et al., Differences in intron-mediated enhancement of gene expression by the first intron of cytosolic superoxide dismutase gene from rice in monocot and dicot plants, Plant Biotech. J., 2012, vol. 29, pp. 115–119. https://doi.org/10.5511/plantbiotechnology.11.1207a

Mun, J.H., Lee, S.Y., Yu, H.J., et al., Petunia actin-depolymerizing factor is mainly accumulated in vascular tissue and its gene expression is enhanced by the first intron, Gene, 2002, vol. 292, nos. 1–2, pp. 233–243. https://doi.org/10.1016/s0378-1119(02)00646-7

Nesic, D., Cheng, J., and Maquat, L.E., Sequences within the last intron function in RNA 3'-end formation in cultured cells, Mol. Cell Biol., 1993, vol. 13, no. 6, pp. 3359–3369. https://doi.org/10.1128/mcb.13.6.3359-3369.1993

Niu, D.K. and Yang, Y.F., Why eukaryotic cells use introns to enhance gene expression: Splicing reduces transcription-associated mutagenesis by inhibiting topoisomerase I cutting activity, Biol. Direct, 2011, vol. 6, p. 24. https://doi.org/10.1186/1745-6150-6-24

O’Sullivan, J.M., Tan-Wong, S.M., Morillon, A., et al., Gene loops juxtapose promoters and terminators in yeast, Nat. Genet., 2004, vol. 36, no. 9, pp. 1014–1018. https://doi.org/10.1038/ng1411

Park, S.G., Hannenhalli, S., and Choi, S.S., Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals, BMC Genomics, 2014, vol. 15, no. 1, p. 526. https://doi.org/10.1186/1471-2164-15-526

Parra, G., Bradnam, K., Rose, A.B., et al., Comparative and functional analysis of intron-mediated enhancement signals reveals conserved features among plants, Nucleic Acids Res., 2011, vol. 39, no. 13, pp. 5328–5337. https://doi.org/10.1093/nar/gkr043

Plesse, B., Criqui, M.C., Durr, A., et al., Effects of the polyubiquitin gene Ubi.U4 leader intron and first ubiquitin monomer on reporter gene expression in Nicotiana tabacum, Plant Mol. Biol., 2001, vol. 45, no. 6, pp. 655–667. https://doi.org/10.1023/a:1010671405594

Proudfoot, N.J., Furger, A., and Dye, M.J., Integrating mRNA processing with transcription, Cell, 2002, vol. 108, no. 4, pp. 501–512. https://doi.org/10.1016/s0092-8674(02)00617-7

Que, Q., Chilton, M.D., de Fontes, C.M., et al., Trait stacking in transgenic crops: challenges and opportunities, GM Crops, 2010, vol. 1, no. 4, pp. 220–229. https://doi.org/10.4161/gmcr.1.4.13439

Rethmeier, N., Seurinck, J., Van Montagu, M., et al., Intron-mediated enhancement of transgene expression in maize is a nuclear, gene-dependent process, Plant J., 1997, vol. 12, no. 4, pp. 895–899. https://doi.org/10.1046/j.1365-313x.1997.12040895.x

Rogozin, I.B., Carmel, L., Csuros, M., et al., Origin and evolution of spliceosomal introns, Biol. Direct, 2012, vol. 7, p. 11. https://doi.org/10.1186/1745-6150-7-11

Rose, A.B., Requirements for intron-mediated enhancement of gene expression in Arabidopsis, RNA, 2002, vol. 8, no. 11, pp. 1444–1453. https://doi.org/10.1017/s1355838202020551

Rose, A.B., The effect of intron location on intron-mediated enhancement of gene expression in Arabidopsis, Plant J., 2004, vol. 40, no. 5, pp. 744–751. https://doi.org/10.1111/j.1365-313X.2004.02247.x

Rose, A.B., Intron-mediated regulation of gene expression, Curr. Top. Microbiol. Immunol., 2008, vol. 326, pp. 277–290. https://doi.org/10.1007/978-3-540-76776-3_15

Rose, A.B., Introns as gene regulators: a brick on the accelerator, Front. Genet., 2019, vol. 9, p. 672. https://doi.org/10.3389/fgene.2018.00672

Rose, A.B. and Beliakoff, J.A., Intron-mediated enhancement of gene expression independent of unique intron sequences and splicing, Plant Physiol., 2000, vol. 122, no. 2, pp. 535–542. https://doi.org/10.1104/pp.122.2.535

Rose, A.B. and Last, R.L., Introns act post-transcriptionally to increase expression of the Arabidopsis thaliana tryptophan pathway gene PAT1, Plant J., 1997, vol. 11, no. 3, pp. 455–464. https://doi.org/10.1046/j.1365-313x.1997.11030455.x

Rose, A.B., Elfersi, T., Parra, G., et al., Promoterproximal introns in Arabidopsis thaliana are enriched in dispersed signals that elevate gene expression, Plant Cell, 2008, vol. 20, no. 3, pp. 543–551. https://doi.org/10.1105/tpc.107.057190

Rose, A.B., Emami, S., Bradnam, K., et al., Evidence for a DNA-based mechanism of intron-mediated enhancement, Front. Plant Sci., 2011, vol. 2, p. 98. https://doi.org/10.3389/fpls.2011.00098

Rose, A.B., Carter, A., Korf, I., et al., Intron sequences that stimulate gene expression in Arabidopsis, Plant Mol. Biol., 2016, vol. 92, no. 3, pp. 337–346. https://doi.org/10.1007/s11103-016-0516-1

Rowlands, C.F., Baralle, D., and Ellingford, J.M., Machine learning approaches for the prioritization of genomic variants impacting pre-mRNA splicing, Cells, 2019, vol. 8, no. 12, p. 1513. https://doi.org/10.3390/cells8121513

Salgueiro, S., Pignocchi, C., and Parry, M.A., Intronmediated gusA expression in tritordeum and wheat resulting from particle bombardment, Plant Mol. Biol., 2000, vol. 42, no. 4, pp. 615–622. https://doi.org/10.1023/a:1006331831858

Samadder, P., Sivamani, E., Lu, J., et al., Transcriptional and post-transcriptional enhancement of gene expression by the 5' UTR intron of rice rubi3 gene in transgenic rice cells, Mol. Genet. Genomics, 2008, vol. 279, no. 4, pp. 429–439. https://doi.org/10.1007/s00438-008-0323-8

Shaul, O., Unique aspects of plant nonsense-mediated mRNA decay, Trends Plant Sci., 2015, vol. 20, no. 11, pp. 767–779. https://doi.org/10.1016/j.tplants.2015.08.011

Shaul, O., How introns enhance gene expression, Int. J. Biochem. Cell Biol., 2017, vol. 91, pp. 145–155. https://doi.org/10.1016/j.biocel.2017.06.016

Shen, X., Jiang, C., Wen, Y., et al., A Brief review on deep learning applications in genomic studies, Front. Syst. Biol., 2022, vol. 2, p. 877717. https://doi.org/10.3389/fsysb.2022.877717

Silva, J.C.F., Teixeira, R.M., Silva, F.F., et al., Machine learning approaches and their current application in plant molecular biology: A systematic review, Plant Sci., 2019, vol. 284, pp. 37–47. https://doi.org/10.1016/j.plantsci.2019.03.020

Simna, S.P. and Han, Z., Prospects of non-coding elements in genomic DNA based gene therapy, Curr. Gene Ther., 2022, vol. 22, no. 2, pp. 89–103. https://doi.org/10.2174/1566523221666210419090357

Sinibaldi, R.M. and Mettler, I.J., Intron splicing and intron-mediated enhanced expression in monocots, Prog. Nucleic Acid Res. Mol. Biol., 1992, vol. 42, pp. 229–257. https://doi.org/10.1016/s0079-6603(08)60577-2

Snowden, K.C., Buchhholz, W.G., and Hall, T.C., Intron position affects expression from the tpi promoter in rice, Plant Mol. Biol., 1996, vol. 31, no. 3, pp. 689–692. https://doi.org/10.1007/BF00042241

Spies, N., Nielsen, C.B., Padgett, R.A., et al., Biased chromatin signatures around polyadenylation sites and exons, Mol. Cell, 2009, vol. 36, no. 2, pp. 245–254. https://doi.org/10.1016/j.molcel.2009.10.008

Tanaka, A., Mita, S., Ohta, S., et al., Enhancement of foreign gene expression by a dicot intron in rice but not in tobacco is correlated with an increased level of mRNA and an efficient splicing of the intron, Nucleic Acids Res., 1990, vol. 18, no. 23, pp. 6767–6770. https://doi.org/10.1093/nar/18.23.6767

To, J.P.C., Davis, I.W., Marengo, M.S., et al., Expression elements derived from plant sequences provide effective gene expression regulation and new opportunities for plant biotechnology traits, Front. Plant Sci., 2021, vol. 12, p. 712179. https://doi.org/10.3389/fpls.2021.712179

Travella, S., Ross, S.M., Harden, J., et al., A comparison of transgenic barley lines produced by particle bombardment and Agrobacterium-mediated techniques, Plant Cell Rep., 2005, vol. 23, no. 12, pp. 780–789. https://doi.org/10.1007/s00299-004-0892-x

Valencia, P., Dias, A.P., and Reed, R., Splicing promotes rapid and efficient mRNA export in mammalian cells, Proc. Natl. Acad. Sci. U. S. A., 2008, vol. 105, no. 9, pp. 3386–3391. https://doi.org/10.1073/pnas.0800250105

Vasil, V., Clancy, M., Ferl, R.J., et al., Increased gene expression by the first intron of maize shrunken-1 locus in grass species, Plant Physiol., 1989, vol. 91, no. 4, pp. 1575–1579. https://doi.org/10.1104/pp.91.4.1575

Vaucheret, H., Béclin, C., Elmayan, T., et al., Transgene-induced gene silencing in plants, Plant J., 1998, vol. 16, no. 6, pp. 651–659. https://doi.org/10.1046/j.1365-313x.1998.00337.x

Vitale, A., Wu, R.J., Cheng, Z., et al., Multiple conserved 5' elements are required for high-level pollen expression of the Arabidopsis reproductive actin ACT1, Plant Mol. Biol., 2003, vol. 52, no. 6, pp. 1135–1151. https://doi.org/10.1023/b:plan.0000004309.06973.16

Weise, A., Rodriguez-Franco, M., Timm, B., et al., Use of Physcomitrella patens actin 5′ regions for high transgene expression: importance of 5' introns, Appl. Microbiol. Biotechnol., 2006, vol. 70, no. 3, pp. 337–345. https://doi.org/10.1007/s00253-005-0087-6

Xiao, G., Zhang, Z.Q., Yin, C.F., et al., Characterization of the promoter and 5'-UTR intron of oleic acid desaturase (FAD2) gene in Brassica napus, Gene, 2014, vol. 545, no. 1, pp. 45–55. https://doi.org/10.1016/j.gene.2014.05.008

Zalabák, D. and Ikeda, Y., First come, first served: sui generis features of the first intron, Plants, 2020, vol. 9, no. 7, p. 911. https://doi.org/10.3390/plants9070911

Zhang, Y., Yan, J., Chen, S., et al., A Review on the application of deep learning in bioinformatics, Curr. Bioinf., 2020, vol. 15, no. 8, pp. 898–911. https://doi.org/10.2174/1574893615999200711165743

Zou, J., Huss, M., Abid, A., et al., A primer on deep learning in genomics, Nat. Genet., 2019, vol. 51, no. 1, pp. 12–18. https://doi.org/10.1038/s41588-018-0295-5