Инд. авторы:	Волкова О.А., Кондрахин Ю.В., Шарипов Р.Н
Заглавие:	Оценка трансляционной значимости характеристик нуклеотидной последовательности мрнк млекопитающих на основе данных рибосомного профилирования
Библ. ссылка:	Волкова О.А., Кондрахин Ю.В., Шарипов Р.Н Оценка трансляционной значимости характеристик нуклеотидной последовательности мрнк млекопитающих на основе данных рибосомного профилирования // Вавиловский журнал генетики и селекции. - 2016. - Т.20. - № 6. - С.779-786. - ISSN 2500-0462. - EISSN 2500-3259.
Внешние системы:	DOI: 10.18699/VJ16.195; РИНЦ: 27641079;
Реферат:	rus: Известно, что характеристики 5'-нетранслируемой последовательности (5'-НТП) мРНК могут оказывать влияние на эффективность и специфичность инициации трансляции. Ранее знания о характеристиках 5'-НТП были получены теоретически и в экспериментах in vitro для мРНК отдельных генов, что не давало возможности оценить реальную трансляционную значимость ее параметров. Для выявления трансляционно-значимых характеристик 5'-НТП необходимо проанализировать их связь с трансляционной активностью соответствующих мРНК. Однако до недавнего времени доступные технологии не позволяли получить широкогеномные экспериментальные данные по эффективности трансляции. Благодаря появившейся технологии профилирования рибосом такие данные были получены для мРНК ряда эукариот. Использование их позволяет оценивать и выявлять трансляционно-значимые параметры мРНК, а также предсказывать эффективность трансляции мРНК на основании характеристик ее нуклеотидной последовательности. Цель нашей работы - определение трансляционной значимости отдельных характеристик нуклеотидной последовательности 5'-НТП мРНК на основании соответствующих экспериментальных данных по эффективности трансляции, рибосомному профилированию. Проведен статистический анализ отдельных характеристик нуклеотидных последовательностей мРНК человека и мыши; выявлена их взаимосвязь с соответствующими данными рибосомного профилирования. Были отобраны трансляционно-значимые параметры мРНК, тенденция влияния на эффективность трансляции которых наиболее значима и одинакова для всех трех проанализированных выборок: пурин в -3-позиции стартового кодона, вышележащие стартовые кодоны AUG в 5'-НТП, и комплементарные нуклеотиды G+C в составе 5'-НТП снижают эффективность трансляции; олигонуклеотид CCGCCA в районе 5'-НТП и олигонуклеотиды AAGAAA, AAGAAG, AAGCAG, AAAAAG в составе белок-кодирующей последовательности - усиливают. Разработаны с помощью платформы BioUML набор инструментов, позволяющий анализировать трансляционную значимость отдельных 5'-НТП мРНК, и программа для предсказания эффективности трансляции мРНК на основании ее нуклеотидной последовательности. eng: It is known that the 5' untranslated region (5' UTR) mRNA characteristics can influence translation initiation efficiency and specificity. Previous knowledge about 5' UTR characteristics was obtained theoretically and in vitro for mRNA of individual genes. It did not allow systematic analysis of mRNA translationally important parameters. To identify the above mentioned 5' UTR characteristics, it is necessary to analyze their relationships with the translational activity of the corresponding mRNAs. Until recently, there were no experimental data on translation efficiency. Thanks to ribosome profiling technology, genome-wide experimental data of translation efficiency have been obtained for many eukaryotic mRNAs. Now it seems to be possible to reveal translationally important mRNA parameters and predict translation efficiency based on their nucleotide sequences. The aim of this study was to determine the translational significance of individual 5' UTR characteristics in accordance with experimental ribosome profiling data. A statistical analysis was carried out for revealing relationships between the human and mouse mRNA nucleotide sequence characteristics and ribosome profiling data. Some of the mRNA parameters influencing translation efficiency were most significant, and the same trends for all three samples analyzed were revealed: a purine at start codon context position -3, upstream AUG (Sl e-mail: ov@bionet.nsc.ru presence and G+C complementary nucleotide concentration reduce translation efficiency; whereas gexonucleotides CCGCCA (5' UTR) and AAGAAA, AAGAAG, AAGCAG, AAAAAG (CDS) increase translation efficiency. A toolkit that allows analyzing the importance of 5' UTR characteristics and a program for prediction of translation efficiency were developed on the base of the BioUML platform.
Ключевые слова:	mRNA; 5 ''UTR; ribosome profiling; инициация трансляции; мРНК; 5''-НТП; Riboseq; профилирование рибосом; translation initiation;
Издано:	2016
Физ. характеристика:	с.779-786
Цитирование:	1. Brar G.A., Yassour M., Friedman N., Regev A., Ingolia N.T., Weissman J.S. High-resolution view of the yeast meiotic program revealed by ribosome profiling. Science. 2012;335:552-557. DOI 10.1126/ science.1215110 2. De Angioletti M., Lacerra G., Sabato V., Carestia C. Beta+45 G--> C: a novel silent beta-thalassaemia mutation, the first in the Kozak sequence. Br. J. Haematol. 2004;124(2):224-231. DOI 10.1046/j.1365-2141.2003.04754.x 3. Dimelow R.J., Wilkinson S.J. Control of translation initiation: a model-based analysis from limited experimental data. J. R. Soc. Interface. 2009;6:51-61. DOI 10.1098/rsif.2008.0221. 4. Ding Y., Shah P., Plotkin J.B. Weak 5'-mRNA secondary structures in short eukaryotic genes. Genome Biol. Evol. 2012;4(10):1046-1053. DOI 10.1093/gbe/evs082. 5. Gerashchenko M., Gladyshev V. Translation inhibitors cause abnormalities in ribosome profiling experiments. Nucl. Acids Res. 2014; 42(17):e134. DOI 10.1093/nar/gku671. 6. Gerashchenko M.V., Lobanov A.V., Gladyshev V.N. Genome-wide ribosome profiling reveals complex translational regulatio in response to oxidative stress. Proc. Natl. Acad. Sci. USA. 2012;109:17394-17399. DOI 10.1073/pnas.1120799109. 7. Godefroy-Colburn T., Thach R.E. The role of mRNA competition in regulating translation. IV. Kinetic model. J. Biol. Chem. 1981;256: 11762-11773. 8. Grünert S., Jackson R.J. The immediate downstream codon strongly influences the efficiency of utilization of eukaryotic translation initiation codons. EMBO J. 1994;13(15):3618-3630. 9. Harkins S., Cornell C.T., Whitton J.L. Analysis of translational initiation in coxsackievirus B3 suggests an alternative explanation for the high frequency of R+4 in the eukaryotic consensus motif. J. Virol. 2005;79(2):987-996. DOI 10.1128/JVI.79.2.987-996.2005. 10. Heiman M., Schaefer A., Gong S., Peterson J.D., Day M., Ramsey K.E., Suarez-Farinas M., Schwarz C., Stephan D.A., Surmeier D.J., Greengard P., Heintz N. A translational profiling approach for the molecular characterization of CNS cell types. Cell. 2008;135(4):738-748. DOI 10.1016/j.cell.2008.10.028. 11. Heinrich R., Rapoport T.A. Mathematical modelling of translation of mRNA in eukaryotes; steady-states, time dependent processes and application to reticulocytes. J. Theor. Biol. 1980;86:279-313. DOI 10.5936/csbj.201204002. 12. Hinnebusch A.G., Lorsch J.R. The Mechanism of eukaryotic translation initiation: new insights and challenges. Cold Spring Harb. Perspect. Biol. 2012;4:a011544. DOI 10.1101/cshperspect.a011544. 13. Ingolia N.T., Brar G.A., Rouskin S., McGeachy A.M., Weissman J.S. The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nat. Protoc. 2012;7(8):1534-1550. DOI 10.1038/nprot.2012.086. 14. Ingolia N.T., Lareau L.F., Weissman J.S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell. 2011;147(4):789-802. DOI 10.1016/j.cell. 2011.10.002. 15. Johannes G., Carter M.S., Eisen M.B., Brown P.O., Sarnow P. Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Proc. Natl. Acad. Sci. USA. 1999;96(23):13118-13123. DOI 10.1073/ pnas.96.23.13118. 16. Kochetov A.V. Alternative translation start sites and hidden coding potential of eukaryotic mRNAs. BioEssays. 2008;30(7):683-691. DOI 10.1002/bies.20771. 17. Kochetov A.V., Palyanov A., Titov I.I., Grigorovich D., Sarai A., Kolchanov N.A. AUG_hairpin: prediction of a downstream secondary structure influencing the recognition of a translation start site. BMC Bioinformatics. 2007;8(1):318. DOI 10.1186/1471-2105-8-318 18. Kozak М. Possible role of flanking nucleotides in recognition of the AUG initiator codon by eukaryotic ribosomes. Nucleic Acids Res. 1981;9(20):5233-5252. DOI 10.1093/nar/9.20.5233. 19. Kozak M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell. 1986;44:283-292. DOI 10.1038/308241a0. 20. Kozak M. An analysis of 5’-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987a;15(20):8125-8148. DOI 10.1093/nar/15.20.8125. 21. Kozak M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. J. Mol. Biol. 1987b;196:947-950. DOI 10.1016/0022-2836(87)90418-9. 22. Kozak M. Context effects and inefficient initiation at non-AUG codons in eukaryotic cell-free translation systems. Mol. Cell. Biol. 1989; 9(11):5073-5080. DOI 10.1128/MCB.9.11.5073. 23. Kozak M. Recognition of AUG and alternative initiator codons is augmented by G in position +4 but is not generally affected by the nucleotides in positions +5 and + 6. EMBO J. 1997;16(9):2482-2492. DOI 10.1093/emboj/16.9.2482. 24. Kozak M. Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene. 2005;361:13-37. DOI 10.1016/j.gene.2005. 06.037. 25. Lee S., Liu B., Lee S., Huang S.X., Shen B., Qian S.B. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl. Acad. Sci. USA. 2012;109(37):E2424-E2432. DOI 10.1073/pnas.1207846109. 26. Li F., Zheng Q., Vandivier L.E., Willmann M.R., Chen Y., Gregory B.D. Regulatory impact of RNA secondary structure across the Arabidopsis transcriptome. Plant Cell. 2012;24:4346-4359. DOI 10.1105/ tpc.112.104232 27. Liu W., Zhao Y., Cui P., Lin Q., Ding F., Xin C., Tan X., Song S., Yu J., Hu S. Thousands of novel transcripts identified in mouse cerebrum, testis, and ES cells based on ribo-minus RNA sequencing. Front. Genet. 2011;2:93. DOI 10.3389/fgene.2011.00093 28. Michel A.M., Choudhury K.R., Firth A.E., Ingolia N.T., Atkins J.F., Baranov P.V. Observation of dually decoded regions of the human genome using ribosome profiling data. Genome Res. 2012;22:2219-2229. DOI 10.1101/gr.133249.111. 29. Na D., Lee S., Lee D. Mathematical modeling of translation initiation for the estimation of its efficiency to computationally design mRNA sequences with desired expression levels in prokaryotes. BMC Syst. Biol. 2010;4:71. DOI 10.1186/1752-0509-4-71. 30. Nakagawa S., Niimura Y., Gojobori T., Tanaka H., Miura K. Diversity of preferred nucleotide sequences around the translation initiation codon in eukaryote genomes. Nucleic Acids Res. 2008;36(3):861-871. DOI 10.1093/nar/gkm1102 31. Niimura Y., Terabe M., Gojobori T., Miura K. Comparative analysis of the base biases at the gene terminal portions in seven eukaryote genomes. Nucleic Acids Res. 2003;31(17):5195-5201. DOI 10.1093/ nar/gkg701. 32. Pestova T.V., Kolupaeva V.G. The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection. Genes Dev. 2002;16:2906-2922. DOI 10.1101/gad.1020902. 33. Pisarev A.V., Kolupaeva V.G., Pisareva V.P., Merrick W.C., Hellen C.U.T., Pestova T.V. Specific functional interactions of nucleotides at key -3 and +4 positions flanking the initiation codon with components of the mammalian 48S translation initiation complex. Genes Dev. 2006;20:624-636. DOI 10.1101/gad.1397906. 34. Reid D.W., Nicchitta C.V. Primary role for endoplasmic reticulum-bound ribosomes in cellular translation identified by ribosome profiling. J. Biol. Chem. 2012;287:5518-5527. DOI 10.1074/jbc. M111.312280. 35. Rogozin I.B., Kochetov A.V., Kondrashov F.A., Koonin E.V., Milanesi L. Presence of ATG triplets in 5' untranslated regions of eukaryotic cDNAs correlates with a ‘weak’ context of the start codon. Bioinformatics. 2001;17(10):890-900. DOI 10.1093/bioinformatics/ 17.10.890 36. Sanz E., Yang L., Su T., Morris D.R., McKnight G.S., Amieux P.S. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc. Natl. Acad. Sci. USA. 2009;106(33):13939-13944. DOI 10.1073/pnas.0907143106 37. Schwanhäusser B., Busse D., Li N., Dittmar G., Schuchhardt J., Wolf J., Chen W., Selbach M. Global quantification of mammalian gene expression control. Nature. 2011;473(7347):337-342. DOI 10.1038/ nature10098 38. Simon Z., Ruckenstein E. Regulation and synthesis processes in the living cell II. Kinetics of protein synthesis. J. Theor. Biol. 1966;11:299-313. DOI 10.1016/0022-5193(66)90167-6 39. Singh C.R., Watanabe R., Chowdhury W., Hiraishi H., Murai M.J., Yamamoto Y., Miles D., Ikeda Y., Asano M., Asano K. Sequential eukaryotic translation initiation factor 5 (eif5) binding to the charged disordered segments of eif4g and eif2ß stabilizes the 48S preinitiation complex and promotes its shift to the initiation mode. Mol. Cell Biol. 2012;32(19):3978-3989. DOI 10.1128/MCB.00376-12 40. Siwiak M., Zielenkiewicz P.A. A comprehensive, quantitative, and genome-wide model of translation. PLoS Comp. Biol. 2010;6(7): e1000865. DOI 10.1371/journal.pcbi.1000865 41. Takacs J.E., Neary T.B., Ingolia N.T., Saini A.K., Martin-Marcos P., Pelletier J., Hinnebusch A.G., Lorsch J.R. Identification of compounds that decrease the fidelity of start codon recognition by the eukaryotic translational machinery. RNA. 2011;17:439-452. DOI 10.1261/rna.2475211 42. Volkova O.A., Kochetov A.V. Interrelations between the nucleotide context of human start AUG codon, N-end amino acids of the encoded protein and initiation of translation. J. Biomol. Struct. Dyn. 2010;27(5):611-618. DOI 10.1080/07391102.2010.10508575 43. Weiss R.B., Atkins J.F. Translation goes global. Science. 2011;334 (6062):1509-1510. DOI 10.1126/science.1216974 44. Xia X., Huang H., Carullo M., Betran E., Moriyama E.N. Conflict between translation initiation and elongation in vertebrate mitochondrial genomes. PLoS ONE. 2007;2:e227. DOI 10.1371/journal.pone. 0000227 45. Zhu L.H., Xu J.X., Zhu S.W., Cai X., Yang S.F., Chen X.L., Guo Q. Gene expression profiling analysis reveals weaning-induced cell cycle arrest and apoptosis in the small intestine of pigs. J. Anim. Sci. 2014;92:996-1006. DOI 10.2527/jas.2013-7551 46. Zong Q., Schummer M., Hood L., Morris D.R. Messenger RNA translation state: the second dimension of high-throughput expression screening. Proc. Natl. Acad. Sci. USA. 1999;96(19):10632-10636. DOI 10.1073/pnas.96.19.10632 47. Zouridis H., Hatzimanikatis V. A model for protein translation: polyzome self-organization leads to maximum protein synthesis rates. Biophys. J. 2007;92:717-730. DOI 10.1529/biophysj.106.087825