Molecular Biology

, Volume 53, Issue 2, pp 157–175 | Cite as

Strategies for Optimizing Recombinant Protein Synthesis in Plant Cells: Classical Approaches and New Directions

  • S. M. RozovEmail author
  • E. V. Deineko


At present, pharmacologically significant proteins are synthesized in different expression systems, from bacterial to mammalian and insect cell cultures. The plant expression systems (especially suspension cell culture) combine the simplicity and low cost of bacterial systems with the ability to perform eukaryotic-type posttranslational protein modifications. A low (compared with bacterial systems) yield of the target recombinant protein is one of the shortcomings of the plant expression systems. In this review, methods, developed over the past two decades, to increase the level of recombinant gene expression and methods to prevent silencing, caused by a random insertion of the target gene into heterochromatin region, are considered. The emergence of CRISPR/Cas technologies led to the creation of a new approach to increase the gene expression level, directional insertion of “pharmaceutical” protein genes in specific, knowingly transcriptionally active genome regions. The plant cell housekeeping gene loci, actively expressed throughout the interphase, are these regions. The organization of some housekeeping genes, most promising for transferring recombinant protein genes in their loci, is considered in detail.


recombinant genes expression optimization pharmaceutical proteins plant cell suspension cultures plant expression systems expression cassettes position effect gene silencing CRISPR/Cas gene targeting genome editing housekeeping genes 



  1. 1.
    Zhu J. 2012. Mammalian cell protein expression for biopharmaceutical production, Biotechnol. Adv. 30, 1158–1170.CrossRefPubMedGoogle Scholar
  2. 2.
    Tekoah Y., Shulman A., Kizhner T., Ruderfer I., Fux L., Nataf Y., Bartfeld D., Ariel T., Gingis-Velitski S., Hanania U., Shaaltiel Y. 2015. Large-scale production of pharmaceutical proteins in plant cell culture: The protalix experience. Plant Biotechnol. J. 13, 1199–1208.CrossRefPubMedGoogle Scholar
  3. 3.
    Naji-Talakar S. 2017. Plant-derived biopharmaceuticals: Overview and success of agroinfiltration. Trends Capstone. 2, 1–12.Google Scholar
  4. 4.
    Ullrich K.K., Hiss M., Rensing S.A. 2015. Means to optimize protein expression in transgenic plants. Curr. Opin. Biotechnol. 32, 61–67.CrossRefPubMedGoogle Scholar
  5. 5.
    Habibi P., Prado G.S., Pelegrini P.B., Hefferon K.L., Soccol C.R., Grossi-de-Sa M.F. 2017. Optimization of inside and outside factors to improve recombinant protein yield in plant. Plant Cell Tissue Organ Culture (PCTOC). 130, 449–467.CrossRefGoogle Scholar
  6. 6.
    Laxa M. 2017. Intron-mediated enhancement: A tool for heterologous gene expression in plants? Front. Plant Sci. 7, 1977.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Saberianfar R., Menassa R. 2018. Strategies to increase expression and accumulation of recombinant proteins. In: Molecular Pharming: Applications, Challenges, and Emerging Areas. Ed. Kermode A.R. New York: Wiley, pp. 119–135.Google Scholar
  8. 8.
    Nandi S., Khush G.S. 2015. Strategies to increase heterologous protein expression in rice grains. In: Recent Advancements in Gene Expression and Enabling Technologies in Crop Plants. New York: Springer, pp. 241‒262.Google Scholar
  9. 9.
    Nocarova E., Fischer L. 2009. Cloning of transgenic tobacco BY-2 cells: An efficient method to analyse and reduce high natural heterogeneity of transgene expression. BMC Plant Biol. 9, 44.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Huang N., Yang D. 2005. ExpressTec: High level expression of biopharmaceuticals in cereal grains. In: Modern Biopharmaceuticals: Design, Development and Optimization. Ed. Knablein J. New York: Wiley VCH, vol. 3, pp. 931–947.Google Scholar
  11. 11.
    Nandi S., Yalda D., Lu S., Nikolov Z., Misaki R., Fujiyama K., Huang N. 2005. Process development and economic evaluation of recombinant human lactoferrin expressed in rice grain. Transgenic Res. 14, 237–249.CrossRefPubMedGoogle Scholar
  12. 12.
    Stolt-Bergner P., Benda C., Bergbrede T., Besir H., Celie P.H., Chang C., Drechsel D., Fischer A., Geerlof A., Giabbai B., Heuvel van den J., Huber G., Knecht W., Lehner A., Lemaitre R., et al. 2018. Baculovirus-driven protein expression in insect cells: A benchmarking study. J. Struct. Biol. 203 (2), 71–80. CrossRefPubMedGoogle Scholar
  13. 13.
    Mader A., Prewein B., Zboray K., Casanova E., Kunert R. 2013. Exploration of BAC versus plasmid expression vectors in recombinant CHO cells. Appl. Microbiol. Biotechnol. 97, 4049–4054.CrossRefPubMedGoogle Scholar
  14. 14.
    Luo M., Gilbert B., Ayliffe M. 2016. Applications of CRISPR/Cas9 technology for targeted mutagenesis, gene replacement and stacking of genes in higher plants. Plant Cell Repts. 35, 1439–1450.CrossRefGoogle Scholar
  15. 15.
    Naqvi S., Farre G., Sanahuja G., Capell T., Zhu C., Christou P. 2010. When more is better: Multigene engineering in plants. Trends Plant Sci. 15, 48–56.CrossRefPubMedGoogle Scholar
  16. 16.
    Geier M., Fauland P., Vogl T., Glieder A. 2015. Compact multi-enzyme pathways in P. pastoris. Chem. Commun. 51, 1643–1646.CrossRefGoogle Scholar
  17. 17.
    Ha S.H., Liang Y.S., Jung H., Ahn M.-J., Suh S.-C., Kweon S.-J., Kim D.-H., Kim Y.-M., Kim J.-K. 2010. Application of two bicistronic systems involving 2A and IRES sequences to the biosynthesis of carotenoids in rice endosperm. Plant Biotechnol. J. 8, 928–938.CrossRefPubMedGoogle Scholar
  18. 18.
    Makhzoum A., Benyammi R., Moustafa K., Trémouillaux-Guiller J. 2014. Recent advances on host plants and expression cassettes’ structure and function in plant molecular pharming. BioDrugs. 28, 145–159.CrossRefPubMedGoogle Scholar
  19. 19.
    Biłas R., Szafran K., Hnatuszko-Konka K., Kononowicz A.K. 2016. cis-Regulatory elements used to control gene expression in plants. Plant Cell, Tissue Organ Culture (PCTOC). 127, 269–287.CrossRefGoogle Scholar
  20. 20.
    Porto M.S., Pinheiro M.P.N., Batista V.G.L., Cavalcanti dos Santos R., de Albuquerque Melo Filho P., de Lima L.M. 2014. Plant promoters: An approach of structure and function. Mol. Biotechnol. 56, 38–49.CrossRefPubMedGoogle Scholar
  21. 21.
    Moustafa K., Makhzoum A., Trémouillaux-Guiller J. 2016. Molecular farming on rescue of pharma industry for next generations. Crit. Rev. Biotechnol. 36, 840–850.CrossRefPubMedGoogle Scholar
  22. 22.
    Hieno A., Naznin H.A., Hyakumachi M., Sakurai T, Tokizawa M., Koyama H., Sato N., Nishiyama T., Hasebe M., Zimmer A.D., Lang D., Reski R., Rensing S.A., Obokata J., Yamamoto Y.Y. 2014. ppdb: plant promoter database version 3.0. Nucleic Acids Res. 42, D1188–D1192.CrossRefPubMedGoogle Scholar
  23. 23.
    Mann D.G.J., King Z.R., Liu W., Joyce B.L., Percifield R.J., Hawkins J.S., LaFayette P.R., Artelt B.J., Burris J.N., Mazarei M., Bennetzen J.L., Parrott W.A., Stewart C.N. 2011. Switchgrass (Panicum virgatum L.) polyubiquitin gene (PvUbi1 and PvUbi2) promoters for use in plant transformation. BMC Biotechnol. 11, 74.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhang J., Martin J.M., Beecher B., Morris C.F., Hannah L.C., Giroux M.J. 2009. Seed-specific expression of the wheat puroindoline genes improves maize wet milling yields. Plant Biotechnol. J. 7 (8), 733–743.CrossRefPubMedGoogle Scholar
  25. 25.
    Qu L.Q., Xing Y.P., Liu W.X., Xu X.P., Song Y.R. 2008. Expression pattern and activity of six glutelin gene promoters in transgenic rice. J. Exp. Bot. 59 (9), 2417–2424.CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Coego A., Brizuela E., Castillejo P., Ruíz S., Koncz C., Del Pozo J. C., Pineiro M., Jarrillo J.A., Paz-Ares J., León J. 2014. The TRANSPLANTA collection of Arabidopsis lines: a resource for functional analysis of transcription factors based on their conditional overexpression. Plant J. 77, 944–953.CrossRefPubMedGoogle Scholar
  27. 27.
    Muller K., Siegel D., Jahnke F.R., Gerrer K., Wend S., Decker E.L., Reski R., Weber W., Zurbriggen M.D. 2014. A red light-controlled synthetic gene expression switch for plant systems. Mol. Biosyst. 10, 1679–1688.CrossRefPubMedGoogle Scholar
  28. 28.
    Liu W., Stewart C.N. 2016. Plant synthetic promoters and transcription factors. Curr. Opin. Biotechnol. 37, 36–44.CrossRefPubMedGoogle Scholar
  29. 29.
    Kim Y., Lee G., Jeon E., Sohn E.J., Lee Y., Kang H., Lee D.W., Kim D.H., Hwang I. 2014. The immediate upstream region of the 5'-UTR from the AUG start codon has a pronounced effect on the translational efficiency in Arabidopsis thaliana. Nucleic Acids Res. 42, 485–498.CrossRefPubMedGoogle Scholar
  30. 30.
    Plotkin J.B., Kudla G. 2011. Synonymous but not the same: The causes and consequences of codon bias. Nat. Rev. Genet. 12, 32–42.CrossRefPubMedGoogle Scholar
  31. 31.
    Simon A.E., Miller W.A. 2013. 3′ Cap-independent translation enhancers of plant viruses. Annu. Rev. Microbiol. 67, 21–42.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Meshcheriakova Y.A., Saxena P., Lomonossoff G.P. 2014. Fine-tuning levels of heterologous gene expression in plants by orthogonal variation of the untranslated regions of a nonreplicating transient expression system. Plant Biotechnol. J. 12, 718–727.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Srivastava A.K., Lu Y., Zinta G., Lang Z., Zhu J.K. 2018. UTR-dependent control of gene expression in plants. Trends Plant Sci. 23, 248–259.CrossRefPubMedGoogle Scholar
  34. 34.
    Laxa M., Müller K., Lange N., Doering L., Pruscha J.T., Peterhänsel C. 2016. The 5' UTR intron of the Arabidopsis GGT1 aminotransferase enhances promoter activity by recruiting RNA polymerase II. Plant Physiol. 172, 313–327.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lu J., Sivamani E., Azhakanandam K., Samadder P., Li X., Qu R. 2008. Gene expression enhancement mediated by the 5′ UTR intron of the rice rubi3 gene varied remarkably among tissues in transgenic rice plants. Mol. Genet. Genom. 279, 563–572.CrossRefGoogle Scholar
  36. 36.
    Scott M.P. 2009. Transgenic maize. Methods Mol. Biol. 526, 6–7.Google Scholar
  37. 37.
    Christensen A.H., Quail P.H. 1996. Ubiquitin promoter-based vectors for high-level expression of selectable and/or screenable marker genes in monocotyledonous plants. Transgenic Res. 5, 213–218.CrossRefPubMedGoogle Scholar
  38. 38.
    Depicker A., Van Montagu M. 1997. Post-transcriptional gene silencing in plants. Curr. Opin. Cell Biol. 9, 373–382.CrossRefPubMedGoogle Scholar
  39. 39.
    Dana A., Tuller T. 2014. The effect of tRNA levels on decoding times of mRNA codons. Nucleic Acids Res. 42, 9171–9181.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gould N., Hendy O., Papamichail D. 2014. Computational tools and algorithms for designing customized synthetic genes. Front. Bioeng. Biotechnol. 2, 41.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gustafsson C., Govindarajan S., Minshull J. 2004. Codon bias and heterologous protein expression. Trends Biotechnol. 22, 346–353.CrossRefPubMedGoogle Scholar
  42. 42.
    Wu G., Zheng Y., Qureshi I., Zin H.T., Beck T., Bulka B., Freeland S.J. 2007. SGDB: A database of synthetic genes re-designed for optimizing protein overexpression. Nucleic Acids Res. 35, D76–D79.CrossRefPubMedGoogle Scholar
  43. 43.
    Franklin S., Ngo B., Efuet E., Mayfield S.P. 2002. Development of a GFP reporter gene for Chlamydomonas reinhardtii chloroplast. Plant J. 30, 733–744.CrossRefPubMedGoogle Scholar
  44. 44.
    Gisby M.F., Mellors P., Madesis P., Ellin M., Laverty H., O’Kane S., Ferguson M.W., Day A. 2011. A synthetic gene increases TGFbeta3 accumulation by 75-fold in tobacco chloroplasts enabling rapid purification and folding into a biologically active molecule. Plant Biotechnol. J. 9, 618–628.CrossRefPubMedGoogle Scholar
  45. 45.
    Kwon K.-C., Chan H.-T., León I.R., Williams-Carrier R., Barkan A., Daniell H. 2016. Codon optimization to enhance expression yields insights into chloroplast translation. Plant Physiol. 172, 62–77.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Komar A.A. 2016. The art of gene redesign and recombinant protein production: Approaches and perspectives. In: Protein Therapeutics. Eds. Sauna Z.E., Kimchi-Sarfati C. Cham, Switzerland: Springer, pp. 161‒177.Google Scholar
  47. 47.
    Komar A.A. 2009. A pause for thought along the co-translational folding pathway. Trends Biochem. Sci. 34, 16–24.CrossRefPubMedGoogle Scholar
  48. 48.
    Kimchi-Sarfaty C., Oh J.M., Kim I.W., Sauna Z.E., Calcagno A.M., Ambudkar S.V., Gottesman M.M. 2007. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 315, 525–528.CrossRefPubMedGoogle Scholar
  49. 49.
    Yu C.H., Dang Y., Zhou Z., Wu C., Zhao F., Sachs M.S., Liu Y. 2015. Codon usage influences the local rate of translation elongation to regulate co-translational protein folding. Mol. Cell. 59, 744–754.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kim S.J., Yoon J.S., Shishido H., Yang Z., Rooney L.A., Barral J.M., Skach W.R. 2015. Protein folding. Translational tuning optimizes nascent protein folding in cells. Science. 348, 444–448.CrossRefPubMedGoogle Scholar
  51. 51.
    Buhr F., Jha S., Thommen M., Mittelstaet J., Kutz F., Schwalbe H., Rodnina M.V., Komar A.A. 2016. Synonymous codons direct cotranslational folding toward different protein conformations. Mol. Cell. 61, 341–351.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Liu J.-X., Howell S.H. 2010. Endoplasmic reticulum protein quality control and its relationship to environmental stress responses in plants. Plant Cell. 22, 2930–2942.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Jang I.C., Niu Q.W., Deng S., Zhao P., Chua N. H. 2012. Enhancing protein stability with retained biological function in transgenic plants. Plant J. 72, 345–354.CrossRefPubMedGoogle Scholar
  54. 54.
    Thomas D.R., Walmsley A.M. 2015. The effect of the unfolded protein response on the production of recombinant proteins in plants. Plant Cell Rep. 34, 179–187.CrossRefPubMedGoogle Scholar
  55. 55.
    Goulet C., Khalf M., Sainsbury F., D’Aous M.-A., Michaud D. 2012. A protease activity-depleted environment for heterologous proteins migrating towards the leaf cell apoplast. Plant Biotechnol. J. 10, 83–94.CrossRefPubMedGoogle Scholar
  56. 56.
    Allshire R.C., Madhani H.D. 2017. Ten principles of heterochromatin formation and function. Nat. Rev. Mol. Cell Biol. 19, 229–244.CrossRefPubMedGoogle Scholar
  57. 57.
    Emery D.W. 2011. The use of chromatin insulators to improve the expression and safety of integrating gene transfer vectors. Hum. Gene Ther. 22, 761–774.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Singer S.D., Liu Z., Cox K.D. 2012. Minimizing the unpredictability of transgene expression in plants: The role of genetic insulators. Plant Cell Rep. 31, 13–25.CrossRefPubMedGoogle Scholar
  59. 59.
    Harraghy N., Gaussin A., Mermod N. 2008. Sustained transgene expression using MAR elements. Curr. Gene Ther. 8, 353–366.CrossRefPubMedGoogle Scholar
  60. 60.
    Wang F., Wang T.Y., Tang Y.Y., Zhang J.H., Yang X.J. 2012. Different matrix attachment regions flanking a transgene effectively enhance gene expression in stably transfected Chinese hamster ovary cells. Gene. 500, 59–62.CrossRefPubMedGoogle Scholar
  61. 61.
    Verma D., Verma M., Dey M., Jain R.K., Wu R. 2005. Molecular dissection of the tobacco Rb7 matrix attachment region (MAR): Effect of 50 half on gene expression in rice. Plant Sci. 169, 704–711.CrossRefGoogle Scholar
  62. 62.
    Chinn A.M., Comai L. 1996. The heat shock cognate 80 gene of tomato is flanked by matrix attachment regions. Plant Mol. Biol. 32, 959–968.CrossRefPubMedGoogle Scholar
  63. 63.
    Oh S.-J., Jeong J.S., Kim E.H., Yi N.R., Yi S.-I., Jang I.-C., Kim Y.S., Suh S.-C., Nahm B.H., Kim J.-K. 2005. Matrix attachment region from the chicken lysozyme locus reduces variability in transgene expression and confers copy number-dependence in transgenic rice plants. Plant Cell Rep. 24, 145–154.CrossRefPubMedGoogle Scholar
  64. 64.
    Butaye K.M.J., Goderis I.J.W.M., Wouters P.F.J., Pues J.M.-T.G., Delaure S.L., Broekaert W.F., Depicker A., Cammue B.P.A., De Bolle M.F.C. 2004. Stable high-level transgene expression in Arabidopsis thaliana using gene silencing mutants and matrix attachment regions. Plant J. 39, 440–449.CrossRefPubMedGoogle Scholar
  65. 65.
    de Bolle M.F.C., Butaye K.M.J., Coucke W.J.W., Goderis I.J.W.M., Wouters P.F.J., van Boxel N., Broekaert W.F., Cammue B.P.A. 2003. Analysis of the influence of promoter elements and a matrix attachment region on the inter-individual variation of transgene expression in populations of Arabidopsis thaliana. Plant Sci. 165, 169–179.CrossRefGoogle Scholar
  66. 66.
    Torney F., Partier A., Says-Lesage V., Nadaud I., Barret P., Beckert M. 2004. Heritable transgene expression pattern imposed onto maize ubiquitin promoter by maize adh-1 matrix attachment regions: tissue and developmental specificity in maize transgenic plants. Plant Cell Rep. 22, 931–938.CrossRefPubMedGoogle Scholar
  67. 67.
    Allen G.C. 2009. The role of nuclear matrix attachment regions in plants. Plant Cell Monogr. 14, 101–129.CrossRefGoogle Scholar
  68. 68.
    Nagaya S., Yoshida K., Kato K., Akasaka K., Shinmyo A. 2001. An insulator element from the sea urchin Hemicentrotus pulcherrimus suppresses variation in transgene expression in cultured tobacco cells. Mol. Genet. Genomics. 265, 405–413.CrossRefPubMedGoogle Scholar
  69. 69.
    She W., Lin W., Zhu Y., Chen Y., Jin W., Yang Y., Han N., Bian H., Zhu M., Wang J. 2010. The gypsy insulator of Drosophila melanogaster, together with its binding protein suppressor of hairywing, facilitate high and precise expression of transgenes in Arabidopsis thaliana. Genetics. 185, 1141–1150.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Huang S., Li X., Yusufzai T.M., Qiu Y., Felsenfeld G. 2007. USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier. Mol. Cell. Biol. 27, 7991–8002.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Dickson J., Gowher H., Strogantsev R., Gaszner M., Hair A., Felsenfeld G., West A.G. 2010. VEZF1 elements mediate protection from DNA methylation. PLoS Genet. 6, e10000804.CrossRefGoogle Scholar
  72. 72.
    Harland L., Crombie R., Anson S., deBoer J., Ioannou P.A., Antoniou M. 2002. Transcriptional regulation of the human TATA binding protein gene. Genomics. 79, 479–482.CrossRefPubMedGoogle Scholar
  73. 73.
    Williams S., Mustoe, T., Mulcahy T., Griffiths M., Simpson D., Antoniou M., Irvine A., Mountain A., Crombie R. 2005. CpG-island fragments from the HNRPA2B1/CBX3 genomic locus reduce silencing and enhance transgene expression from the hCMV promoter/enhancer in mammalian cells. BMC Biotechnol. 5, 17.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Majocchi S., Aritonovska E., Mermod N. 2014. Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes. Nucleic Acids Res. 42, 193–204.CrossRefPubMedGoogle Scholar
  75. 75.
    Simpson D.J., Williams S.G., Irvine A.S. 2009. US Patent No. US7632661 B2. Washington, DC: U.S. Patent and Trademark Office.Google Scholar
  76. 76.
    Neville J.J., Orlando J., Mann K., McCloskey B., Antoniou M.N. 2017. Ubiquitous chromatin-opening elements (UCOEs): Applications in biomanufacturing and gene therapy. Biotechnol. Adv. 35, 557–564.CrossRefPubMedGoogle Scholar
  77. 77.
    Saunders F., Sweeney B., Antoniou M.N., Stephens P., Cain K. 2015. Chromatin function modifying elements in an industrial antibody production platform-comparison of UCOE, MAR, STAR and cHS4 elements. PLoS One. 10, e0120096.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Kwaks T.H., Barnett P., Hemrika W., Siersma T., Sewalt R.G., Satijn D.P.E., Brons J.F., van Blokland R., Kwakman P., Kruckeberg A.L., Kelder A., Otte A.P. 2003. Identification of anti-repressor elements that confer high and stable protein production in mammalian cells. Nat. Biotechnol. 21, 553–558.CrossRefPubMedGoogle Scholar
  79. 79.
    Zboray K., Sommeregger W., Bogner E., Gili A., Sterovsky T., Fauland K., Grabner B., Stiedl P., Moll H.P., Bauer A., Kunert R., Casanova E. 2015. Heterologous protein production using euchromatin-containing expression vectors in mammalian cells. Nucl. Acids Res. 43, e102–e102.CrossRefPubMedGoogle Scholar
  80. 80.
    Van Keuren M.L., Gavrilina G.B., Filipiak W.E., Zeidler M.G., Saunders T.L. 2009. Generating transgenic mice from bacterial artificial chromosomes: transgenesis efficiency, integration and expression outcomes. Transgenic Res. 18, 769–785.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ahmadi S., Davami F., Davoudi N., Nematpour F., Ahmadi M., Ebadat S., Azadmanesh K., Barkhordari F., Mahboudi F. 2017. Monoclonal antibodies expression improvement in CHO cells by PiggyBac transposition regarding vectors ratios and design. PLoS One. 12, e0179902.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Dupuy A.J., Fritz S., Largaespada D.A. 2001. Transposition and gene disruption in the male germline of the mouse. Genesis. 30, 82–88.CrossRefPubMedGoogle Scholar
  83. 83.
    Horie K., Yusa K., Yae K., Odajima J., Fischer S.E., Keng V.W., Hayakawa T., Mizuno S., Kondoh G., Ijiri T., Matsuda Y., Plasterk R.H.A., Takeda J. 2003. Characterization of Sleeping Beauty transposition and its application to genetic screening in mice. Mol. Cell. Biol. 23, 9189–9207.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Fraser M.J., Ciszczon T., Elick T., Bauser C. 1996. Precise excision of TTAA specific lepidopteran transposons piggyBac (IFP2) and tagalong (TFP3) from the baculovirus genome in cell lines from two species of Lepidoptera. Insect Mol. Biol. 5, 141–151.CrossRefPubMedGoogle Scholar
  85. 85.
    Li R., Zhuang Y., Han M., Xu T., Wu X. 2013. piggyBac as a high capacity transgenesis and gene-therapy vector in human cells and mice. Dis. Models. J. Mech. 6, 828–833.CrossRefGoogle Scholar
  86. 86.
    Wang Y., Yau Y.-Y., Perkins-Balding D., Thompson J.G. 2011. Recombinase technology: Applications and possibilities. Plant Cell Rep. 30, 267–285.CrossRefPubMedGoogle Scholar
  87. 87.
    Lee G., Saito I. 1998. Role of nucleotide sequences of loxP spacer region in Cre-mediated recombination. Gene. 216, 55–65.CrossRefPubMedGoogle Scholar
  88. 88.
    Turan S., Kuehle J., Schambach A., Baum C., Bode J. 2010. Multiplexing RMCE: Versatile extensions of the Flp-recombinase-mediated cassette-exchange technology. J. Mol. Biol. 402, 52–69.CrossRefPubMedGoogle Scholar
  89. 89.
    Turan S., Galla M., Ernst E., Qiao J., Voelkel C., Bode J. 2011. Recombinase-mediated cassette exchange (RMCE): Traditional concepts and current challenges. J. Mol. Biol. 407, 193–221.CrossRefPubMedGoogle Scholar
  90. 90.
    Baumann M., Gludovacz E., Sealover N., Bahr S., George H., Lin N., Kayser K., Borth N. 2017. Preselection of recombinant gene integration sites enabling high transcription rates in CHO cells using alternate start codons and recombinase mediated cassette exchange. Biotechnol. Bioeng. 114, 2616–2627.CrossRefPubMedGoogle Scholar
  91. 91.
    Sheshukova E.V., Komarova T.V., Dorokhov Y.L. 2016. Plant factories for the production of monoclonal antibodies. Biochemistry (Moscow). 81 (10), 1118–1135.PubMedGoogle Scholar
  92. 92.
    Komarova T.V., Sheshukova E.V., Dorokhov Y.L. 2018. Plant-made antibodies: Properties and therapeutic applications. Curr. Med. Chem. 25, 1–15.CrossRefGoogle Scholar
  93. 93.
    Yamauchi T., Iida S. 2015. Gene targeting in crop species with effective selection systems. In: Advances in New Technology for Targeted Modification of Plant Genomes. Eds. Zhang F., Puchta H., Thomson J.G. New York: Springer, pp. 91–111.Google Scholar
  94. 94.
    Doetschman T., Gregg R.G., Maeda N., Hooper M.L., Melton D.W., Thompson S., Smithies, O. 1987. Targeted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature. 330, 576–578.CrossRefPubMedGoogle Scholar
  95. 95.
    Thomas K.R., Capecchi M.R. 1987. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 51, 503–512.CrossRefPubMedGoogle Scholar
  96. 96.
    Paszkowski J., Baur M., Bogucki A., Potrykus I. 1988. Gene targeting in plants. EMBO J. 7, 4021–4026.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Puchta H., Fauser F. 2013. Gene targeting in plants: 25 years later. Int. J. Dev. Biol. 57, 629–637.CrossRefPubMedGoogle Scholar
  98. 98.
    Shaked H., Melamed-Bessudo C., Levy A.A. 2005. High-frequency gene targeting in Arabidopsis plants expressing the yeast RAD54 gene. Proc. Natl. Acad. Sci. U. S. A. 102, 12265–12269.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Da Ines O., White C.I. 2013. Gene site-specific insertion in plants. In: Topics in Current Genetica. Eds. Renault S., Duchateau P. Springer, vol. 23, pp. 287–315.Google Scholar
  100. 100.
    Chapman J.R., Taylor M.R., Boulton S.J. 2012. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell. 47, 497–510.CrossRefPubMedGoogle Scholar
  101. 101.
    Voytas D.F. 2013. Plant genome engineering with sequence-specific nucleases. Annu. Rev. Plant. Biol. 64, 327–350.CrossRefPubMedGoogle Scholar
  102. 102.
    Urnov F.D., Rebar E.J., Holmes M.C., Zhang H.S., Gregory P.D. 2010. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11, 636–646.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Carroll D. 2011. Genome engineering with zinc-finger nucleases. Genetics. 188, 773–782.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Christian M., Cermak T., Doyle E.L., Schmidt C., Zhang F., Hummel A., Bogdanove A.J., Voytas D.F. 2010. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 186, 757–761.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Christian M., Voytas D.F. 2015. Engineered TAL effector proteins: Versatile reagents for manipulating plant genomes. In: Advances in New Technology for Targeted Modification of Plant Genomes. Eds. Zhang F., Puchta H., Thomson J.G. New York: Springer, pp. 55–72.Google Scholar
  106. 106.
    Sprink T., Metje J., Hartung F. 2015. Plant genome editing by novel tools: TALEN and other sequence specific nucleases. Curr. Opin. Biotechnol. 32, 47–53.CrossRefPubMedGoogle Scholar
  107. 107.
    Barnett P. 2018. Transcription activator like effector nucleases (TALENs): A new, important, and versatile gene editing technique with a growing literature. Sci. Technol. Libraries. 37, 100–112.CrossRefGoogle Scholar
  108. 108.
    Cong L., Ran F.A., Cox D., Lin S., Barretto R., Habib N., Hsu P.D., Wu X., Jiang W., Marraffini L., Zhang F. 2013. Multiplex genome engineering using CRISPR/ Cas systems. Science. 1231143.Google Scholar
  109. 109.
    Makarova K.S., Haft D.H., Barrangou R., Brouns S.J., Charpentier E., Horvath P., Moineau S.A., Mojica F.J.M., Wolf Y.I., Yakunin A.F., van der Oost J., Koonin E.V. 2011. Evolution and classification of the CRISPR–Cas systems. Nat. Rev. Microbiol. 9, 467–477.CrossRefPubMedGoogle Scholar
  110. 110.
    Ran F.A., Hsu P.D., Wright J., Agarwala V., Scott D.A., Zhang F. 2013. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Hsu P.D., Lander E.S., Zhang F. 2014. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 157, 1262–1278.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. 2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 337, 816–821.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Brazelton Jr, V.A., Zarecor S., Wright D.A., Wang Y., Liu J., Chen K., Yang B., Lawrence-Dill C.J. 2015. A quick guide to CRISPR sgRNA design tools. GM Crops Food. 6, 266–276.CrossRefPubMedGoogle Scholar
  114. 114.
    Ma X., Zhu Q., Chen Y., Liu Y.G. 2016. CRISPR/ Cas9 platforms for genome editing in plants: Developments and applications. Mol. Plant. 9, 961–974.CrossRefPubMedGoogle Scholar
  115. 115.
    Puchta H. 2017. Applying CRISPR/Cas for genome engineering in plants: The best is yet to come. Curr. Opin. Plant Biol. 36, 1–8.CrossRefPubMedGoogle Scholar
  116. 116.
    Khan M.H.U., Khan S.U., Muhammad A., Hu L., Yang Y., Fan C. 2018. Induced mutation and epigenetics modification in plants for crop improvement by targeting CRISPR/Cas9 technology. J. Cell. Physiol. 233, 4578–4594.CrossRefPubMedGoogle Scholar
  117. 117.
    Bannikov A.V., Lavrov A.V. 2017. CRISPR/Cas9, the king of genome editing tools. Mol. Biol. (Moscow). 51 (4), 514–525.CrossRefGoogle Scholar
  118. 118.
    Bayat H., Modarressi M.H., Rahimpour A. 2018). The conspicuity of CRISPR-Cpf1 system as a significant breakthrough in genome editing. Curr. Microbiol. 75, 107–115.CrossRefPubMedGoogle Scholar
  119. 119.
    Langner T., Kamoun S., Belhaj K. 2018. CRISPR Crops: Plant genome editing toward disease resistance. Ann. Rev. Phytopathol. 56, 479–512.CrossRefGoogle Scholar
  120. 120.
    Lee K., Zhang Y., Kleinstiver B.P., Guo J.A., Aryee M.J., Miller J., Malzahn A., Zarecor S., Lawrence-Dill C.J., Joung J.K., Qi Y., Wang K. 2018. Activities and specificities of CRISPR/Cas9 and Cas12a nucleases for targeted mutagenesis in maize. Plant Biotechnol. J.
  121. 121.
    Li S., Zhang X., Wang W., Guo X., Wu Z., Du W., Zhao Y., Xia L. 2018. Expanding the scope of CRISPR/Cpf1-mediated genome editing in rice. Mol. Plant. 11, 995–998.CrossRefPubMedGoogle Scholar
  122. 122.
    Gerlach W.L., Bedbrook J.R. 1979. Cloning and characterization of ribosomal RNA genes from wheat and barley. Nucleic Acids Res. 7, 1869–1885.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Hemleben V., Zentgraf U. 1994. Structural organization and regulation of transcription by RNA polymerase I of plant nuclear ribosomal RNA genes. In: Plant Promoters and Transcription Factors. Berlin: Springer, pp. 3‒24.Google Scholar
  124. 124.
    Garcia S., Cortes P.P., Fernàndez X., Garnatje T., Kovarik A. 2016. Organization, expression and evolution of rRNA genes in plant genomes. In: Recent Advances in Pharmaceutical Sciences. Eds. Muñoz-Torrero D., Domínguez A., Manresa A. Barcelona: Presas, vol. 6, pp. 49–75.Google Scholar
  125. 125.
    Copenhaver G.P., Pikaard C.S. 1996. RFLP and physical mapping with an rDNA-specific endonuclease reveals that nucleolus organizer regions of Arabidopsis thaliana adjoin the telomeres on chromosomes 2 and 4. Plant J. 9, 259–272.CrossRefPubMedGoogle Scholar
  126. 126.
    Chandrasekhara C., Mohannath G., Blevins T., Pontvianne F., Pikaard C.S. 2016. Chromosome-specific NOR inactivation explains selective rRNA gene silencing and dosage control in Arabidopsis. Genes Dev. 30, 177–190.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Earley K.W., Pontvianne F., Wierzbicki A.T., Blevins T., Tucker S., Costa-Nunes P., Pontes, O.M., Pikaard C.S. 2010. Mechanisms of HDA6-mediated rRNA gene silencing: Suppression of intergenic Pol II transcription and differential effects on maintenance versus siRNA-directed cytosine methylation. Genes Dev. 24, 1119–1132.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Mohannath G., Pontvianne F., Pikaard C.S. 2016. Selective nucleolus organizer inactivation in Arabidopsis is a chromosome position-effect phenomenon. Proc. Natl. Acad. Sci. U. S. A. 113, 13426–13431.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Gruendler P., Unfried I., Pascher K., Schweizer D. 1991. rDNA intergenic region from Arabidopsis thaliana. Structural analysis, intraspecific variation and functional implications. J. Mol. Biol. 221, 1209–1222.CrossRefPubMedGoogle Scholar
  130. 130.
    Doelling J.H., Gaudino R.J., Pikaard C.S. 1993. Functional analysis of Arabidopsis thaliana rRNA gene and spacer promoters in vivo and by transient expression. Proc. Natl. Acad. Sci. U. S. A. 90, 7528–7532.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Drouin G., De Sa M.M. 1995. The concerted evolution of 5S ribosomal genes linked to the repeat units of other multigene families. Mol. Biol. Evol. 12, 481–493.PubMedGoogle Scholar
  132. 132.
    Campell B.R., Song Y., Posch T.E., Cullis C.A., Town C.D. 1992. Sequence and organization of 5S ribosomal RNA encoding genes of Arabidopsis thaliana. Gene. 112, 225–228.CrossRefPubMedGoogle Scholar
  133. 133.
    Fransz P., Armstrong S., Alonso-Blanco C., Fischer T.C., Torres-Ruiz R.A., Jones G. 1998. Cytogenetics for the model system Arabidopsis thaliana. Plant J. 13, 867–876.CrossRefPubMedGoogle Scholar
  134. 134.
    Cloix C., Tutois S., Yukawa Y., Mathieu O., Cuvilier C., Espagnol M.-C., Picard G., Tourmente S. 2002. Analysis of the 5S RNA pool in Arabidopsis thaliana: RNAs are heterogeneous and only two of the genomic 5S loci produce mature 5S RNA. Genome Res. 12, 132–144.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Mathieu O., Jasencakova S., Vaillant I., Gendrel A.-V., Colot V., Schubert I., Tourmente S. 2003. Changes in 5S rDNA chromatin organization and transcription during heterochromatin establishment in Arabidopsis. Plant Cell. 15, 2929–2939.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Maréchal-Drouard L., Weil J.H., Dietrich A. 1993. Transfer RNAs and transfer RNA genes in plants. Annu. Rev. Plant Biol. 44, 13–32.CrossRefGoogle Scholar
  137. 137.
    Beier D., Stange N., Gross H.J., Beier H. 1991. Nuclear tRNA Tyr genes are highly amplified at a single chromosomal site in the genome of Arabidopsis thaliana. Mol. Gen. Genet. 225, 72–80.CrossRefPubMedGoogle Scholar
  138. 138.
    Arimbasseri A.G., Maraia R.J. 2016. RNA polymerase III advances: Structural and tRNA functional views. Trends Biochem. Sci. 41, 546–559.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Eirín-López J.M., González-Romero R., Dryhurst D., Méndez J., Ausió J. 2009. Long-term evolution of histone families: Old notions and new insights into their mechanisms of diversification across eukaryotes. In: Evolutionary Biology. Ed. Pontarotti P. Berlin: Springer, pp. 139–162.Google Scholar
  140. 140.
    Chaubet N., Philipps G., Gigot C. 1989. Organization of the histone H3 and H4 multigenic families in maize and in related genomes. Mol. Gen. Genet. 219, 404–412.CrossRefGoogle Scholar
  141. 141.
    Kanazin V., Blake T., Shoemaker R.C. 1996. Organization of the histone H3 genes in soybean, barley and wheat. Mol. Gen. Genet. 250, 137–147.CrossRefPubMedGoogle Scholar
  142. 142.
    Li M., Fang Y. 2015. Histone variants: The artists of eukaryotic chromatin. Sci. China Life Sci. 58, 232–239.CrossRefPubMedGoogle Scholar
  143. 143.
    Ingouff M., Berger F. 2010. Histone3 variants in plants. Chromosoma. 119, 27–33.CrossRefPubMedGoogle Scholar
  144. 144.
    Kosterin O.E., Bogdanova V.S., Gorel F.L., Rozov S.M., Trusov Y.A., Berdnikov V.A. 1994. Histone H1 of the garden pea (Pisum sativum L.): Composition, developmental changes, allelic polymorphism and inheritance. Plant Sci. 101, 189–202.CrossRefGoogle Scholar
  145. 145.
    Henikoff S., Ahmad K. 2005. Assembly of variant histones into chromatin. Annu. Rev. Cell. Dev. Biol. 21, 133–153.CrossRefPubMedGoogle Scholar
  146. 146.
    McDowell J.M., Huang S., McKinney E.C., An Y.Q., Meagher R.B. 1996. Structure and evolution of the actin gene family in Arabidopsis thaliana. Genetics. 142, 587–602.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Šlajcherová K., Fišerová J., Fischer L., Schwarzerová K. 2012. Multiple actin isotypes in plants: Diverse genes for diverse roles? Front. Plant Sci. 3, 226.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Silflow C.D., Oppenheimer D.G., Kopozak S.D., Ploense S.E., Ludwig S.R., Haas N., Peter Snustad D. 1987. Plant tubulin genes: Structure and differential expression during development. Genesis. 8, 435–460.Google Scholar
  149. 149.
    Oakley R.V., Wang Y.S., Ramakrishna W., Harding S.A., Tsai C.J. 2007. Differential expansion and expression of α-and β-tubulin gene families in Populus. Plant Physiol. 145, 961–973.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Breviario D. 2008. Plant tubulin genes: Regulatory and evolutionary aspects. In: Plant Microtubules. Plant Cell Monographs. Ed. Nick P. Berlin, Heidelberg: Springer, vol. 11, pp. 207–232.Google Scholar
  151. 151.
    Callis J., Carpenter T., Sun C.W., Vierstra R.D. 1995. Structure and evolution of genes encoding polyubiquitin and ubiquitin-like proteins in Arabidopsis thaliana ecotype Columbia. Genetics. 139, 921–939.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Callis J. 2014. The ubiquitination machinery of the ubiquitin system. The Arabidopsis Book, 12, e0174.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Radici L., Bianchi M., Crinelli R., Magnani M. 2013. Ubiquitin C gene: Structure, function, and transcriptional regulation. Adv. Biosci. Biotechnol. 4, 1057–1062.CrossRefGoogle Scholar
  154. 154.
    Bachmair A., Finley D., Varshavsky A. 1986. In vivo half-life of a protein is a function of its amino-terminal residue. Science. 234, 179–186.CrossRefPubMedGoogle Scholar
  155. 155.
    Gonda D., Bachmair A., Wunning I., Tobias J., Lane W., Varshavsky A. 1989. Universality and structure of the N-end rule. J. Biol. Chem. 264, 16700–16712.PubMedGoogle Scholar
  156. 156.
    Hondred D., Walker J.M., Mathews D.E., Vierstra R.D. 1999. Use of ubiquitin fusions to augment protein expression in transgenic plants. Plant Physiol. 119, 713–724.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  1. 1.Federal Research Center Institute of Cytology and Genetics, Siberian Branch, Russian Academy of SciencesNovosibirskRussia
  2. 2.Tomsk State UniversityTomskRussia

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