Use of MAR Elements to Increase the Production of Recombinant Proteins

  • Cori Gorman
  • Salina Arope
  • Mélanie Grandjean
  • Pierre-Alain Girod
  • Nicolas Mermod
Chapter
Part of the Cell Engineering book series (CEEN, volume 6)

Abstract

The biopharmaceutical industry continues to face the challenge of producing large amount of recombinant proteins for use as therapeutics, and eighty percent of protein therapeutics in clinical development are produced in mammalian cell systems. Approaches to increase production addressing growth conditions, such as the improvement of media composition and process control, or transcription of the recombinant gene via the use of strong promoters/enhancers and amplification of gene copy number, have increased the yields obtained from mammalian cells considerably over the past decades. However these processes remain laborious, and extensive screening of clones is often required, as stable cell line and/or protein production is not always obtained. Unstable or variable expression is linked to the location of transgene integration site, the regulation of gene expression, the silencing of genes, and the loss of gene copies. Genetic elements that may remodel chromatin to maintain the transgene in an active configuration are now being employed increasingly to improve protein production using mammalian cells. Here we will review how one type of such elements, the MARs, may increase transgene integration into the cell genome and decrease silencing effects to reduce expression variability. We also illustrate how inclusion of these elements in expression vectors leads to increased specific productivities ranging from 20 to 100 picograms per cell and per day (p/c/d), resulting in protein titers above 5 g/l.

References

  1. Allen G, Hall GJ, Michalowski S, Newman W, Spiker S, Weissinger A, Thompson W (1996) High-level transgene expression in plant cells: effects of a strong scaffold attachment region from tobacco. Plant Cell 8:899–913PubMedCrossRefGoogle Scholar
  2. Almeida R, Robin C (2005) RNA silencing and genome regulation. Trends Cell Biol 15:251–258PubMedCrossRefGoogle Scholar
  3. Andrulis IL, Duff C, Evans-Blackler S, Worton R, Siminovitch L (1983) Chromosomal alterations associated with overproduction of asparagine synthetase in albizziin-resistant Chinese hamster ovary cells. Mol Cell Biol 3:391–398PubMedGoogle Scholar
  4. Baldassarre G, Fedele M, Battista S, Vecchione A, Klein-Szanto AJ, Santoro M, Waldmann TA, Azimi N, Croce CM, Fusco A (2001) Onset of natural killer cell lymphomas in transgenic mice carrying a truncated HMGI-C gene by the chronic stimulation of the IL-2 and IL-15 pathway. Proc Natl Acad Sci USA 98:7970–7975PubMedCrossRefGoogle Scholar
  5. Barnes LM, Dickson AJ (2006) Mammalian cell factories for efficient and stable protein expression. Curr Opin Biotech 17:381–386PubMedCrossRefGoogle Scholar
  6. Barnes LM, Bentley CM, Dickson AJ (2001) Characterization of the stability of recombinant protein production in the GS-NS0 expression system. Biotechnol Bioeng 73:261–270PubMedCrossRefGoogle Scholar
  7. Barnes LM, Bentley CM, Dickson AJ (2003) Stability of protein production from recombinant mammalian cells. Biotechnol Bioeng 81:631–639PubMedCrossRefGoogle Scholar
  8. Barnes LM, Bentley CM, Dickson AJ (2004) Molecular definition of predictive indicators of stable protein expression in recombinant NS0 myeloma cells. Biotechnol Bioeng 85:115–121PubMedCrossRefGoogle Scholar
  9. Barnes LM, Moy N, Dickson AJ (2006b) Phenotypic variation during cloning procedures: analysis of the growth behavior of clonal cell lines. Biotechnol Bioeng 94:530–537PubMedCrossRefGoogle Scholar
  10. Barnes LM, Bentley CM, Moy N, Dickson AJ (2007) Molecular analysis of successful cell line selection in transfected GS-NS0 myeloma cells. Biotechnol Bioeng 96:337–348PubMedCrossRefGoogle Scholar
  11. Baur JA, Shay JW, Wright WE (2004) Spontaneous reactivation of a silent telomeric transgene in a human cell line. Chromosoma 112:240–246PubMedCrossRefGoogle Scholar
  12. Bode J, Kohwi Y, Dickinson L, Joh T, Klehr D, Mielke C, Kohwi-Shigematsu T (1992) Biological significance of unwinding capability of nuclear matrix-associating DNAs. Science 255:195–197PubMedCrossRefGoogle Scholar
  13. Bode J, Stengert-Iber M, Kay V, Schlake T, Dietz-Pfeilstetter A (1996) Scaffold/matrix-attached regions: topological switches with multiple regulatory functions. Crit Rev Eukaryot Gene Expr 6:115–138PubMedGoogle Scholar
  14. Bode J, Goetze S, Heng H, Krawetz SA, Benham C (2003) From DNA structure to gene expression: mediators of nuclear compartmentalization and dynamics. Chromosome Res 11:435–445PubMedCrossRefGoogle Scholar
  15. Bode J, Winkelmann S, Gotze S, Spiker S, Tsutsui K, Bi C, A KP, Benham C (2006) Correlations between scaffold/matrix attachment region (S/MAR) binding activity and DNA duplex destabilization energy. J Mol Biol 358:597–613PubMedCrossRefGoogle Scholar
  16. Bonifer C, Vidal M, Grosveld F, Sippel AE (1990) Tissue specific and position independent expression of the complete gene domain for chicken lysozyme in transgenic mice. EMBO J 9:2843–2848PubMedGoogle Scholar
  17. Bonifer C, Yannoutsos N, Kruger G, Grosveld F, Sippel AE (1994) Dissection of the locus control function located on the chicken lysozyme gene domain in transgenic mice. Nucl Acids Res 22:4202–4210PubMedCrossRefGoogle Scholar
  18. Boulikas T (1993) Nature of DNA sequences at the attachment regions of genes to the nuclear matrix. J Cell Biochem 52:14–22PubMedCrossRefGoogle Scholar
  19. Cai S, Han HJ, Kohwi-Shigematsu T (2003) Tissue-specific nuclear architecture and gene expression regulated by SATB1. Nat Genet 34:42–51PubMedCrossRefGoogle Scholar
  20. Cai S, Lee CC, Kohwi-Shigematsu T (2006) SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet 38:1278–1288PubMedCrossRefGoogle Scholar
  21. Chung JH, Whiteley M, Felsenfeld G (1993) A 5′ element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell 74:505–514PubMedCrossRefGoogle Scholar
  22. Clark DJ, Felsenfeld G (1991) Formation of nucleosomes on positively supercoiled DNA. EMBO J 10:387–395PubMedGoogle Scholar
  23. Cui T, Leng F (2007) Specific recognition of AT-rich DNA sequences by the mammalian high mobility group protein AT-hook 2: a SELEX study. Biochemistry 46:13059–13066PubMedCrossRefGoogle Scholar
  24. Derouazi M, Martinet D, Besuchet Schmutz N, Flaction R, Wicht M, Bertschinger M, Hacker DL, Beckmann JS, Wurm FM (2006) Genetic characterization of CHO production host DG44 and derivative recombinant cell lines. Biochem Biophys Res Commun 340:1069–1077PubMedCrossRefGoogle Scholar
  25. Dickinson LA, Joh T, Kohwi Y, Kohwi-Shigematsu T (1992) A tissue-specific MAR/SAR DNA-binding protein with unusual binding site recognition. Cell 70:631–645PubMedCrossRefGoogle Scholar
  26. Eissenberg JC (1989) Position effect variegation in Drosophila: Towards genetics of chromatin assembly. Bioessays 11:14–17PubMedCrossRefGoogle Scholar
  27. Eissenberg JC, Morris GD, Reuter G, Hartnett T (1992) The heterochromatin-associated protein HP-1 is an essential protein in Drosophila with dosage-dependent effects on position-effect variegation. Genetics 131:345–352PubMedGoogle Scholar
  28. Esnault G, Majocchi S, Martinet D, Besuchet-Schmute N, Beckmann JS, Mermod N (2009) Transcription factor CTFA acts as a chromatin domain boundary that Shields human telomeric genes from silencing. Moll Cell Biol 29:2409–2418CrossRefGoogle Scholar
  29. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159PubMedCrossRefGoogle Scholar
  30. Evans K, Ott S, Hansen A, Koentges G, Wernisch L (2007) A comparative study of S/MAR prediction tools. BMC Bioinformatics 8:71–100PubMedCrossRefGoogle Scholar
  31. Fann CH, Guirgis F, Chen G, Lao MS, Oiret JM (2000) Limitations to the amplification and stability of human tissue-type plasminogen activator expression by Chinese hamster ovary cells. Biotechnol Bioeng 69:204–12PubMedCrossRefGoogle Scholar
  32. Fedoriw AM, Engel NI, Bartolomei MS (2004) Genomic imprinting: antagonistic mechanisms in the germ line and early embryo. Cold Spring Harb Symp Quant Biol 69:39–45PubMedGoogle Scholar
  33. Feinberg AP (2008) Epigenetics at the epicenter of modern medicine. JAMA 299:1345–1350PubMedCrossRefGoogle Scholar
  34. Felsenfeld G (1992) Chromatin as an essential part of the transcriptional mechanism. Nature 355:219–224PubMedCrossRefGoogle Scholar
  35. Felsenfeld G (1996) Chromatin unfolds. Cell 86:13–19PubMedCrossRefGoogle Scholar
  36. Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV (1996) An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol 16:2802–2813PubMedGoogle Scholar
  37. Flintoff WF, Livingston E, Duff C, Worton RG (1984) Moderate-level gene amplification in methotrexate-resistant Chinese hamster ovary cells is accompanied by chromosomal translations at or near the site of amplified DHFR gene. Mol Cell Biol 4:69–76PubMedGoogle Scholar
  38. Folger KR, Wong EA, Wahl G, Capecchi MR (1982) Patterns of integration of DNA microinjected into cultured mammalian cells: evidence for homologous recombination between injected plasmid DNA molecules. Mol Cell Biol 2:1372–1387PubMedGoogle Scholar
  39. Folger KR, Thomas K, Capecchi MR (1985) Nonreciprocal exchanges of information between DNA duplexes coinjected into mammalian cell nuclei. Mol Cell Biol 5:59–69PubMedGoogle Scholar
  40. Forrester WC, Novak U, Gelinas R, Groudine M (1989) Molecular analysis of the human beta-globin locus activation region. Proc Natl Acad Sci USA 86:5439–5443PubMedCrossRefGoogle Scholar
  41. Fouremana P, Winfield JA, Peter J, Hahnb PJ (1998) Chromosome breakpoints near CpG islands in double minutes. Gene 218:121–128CrossRefGoogle Scholar
  42. Galande S, Purbey PK, Notani D, Kumar PP (2007) The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1. Curr Opin Genet Dev 17:408–414PubMedCrossRefGoogle Scholar
  43. Galbete JL, Buceta M, Mermod N (2009) MAR elements regulate the probability of epigenetic switching between active and inactive gene expression. Mol Biosyst 5:143–150Google Scholar
  44. Gaszner M, Felsenfeld G (2006) Insulators: exploiting transcriptional and epigenetic mechanisms. Nat Rev Genet 7:703–713PubMedCrossRefGoogle Scholar
  45. Gilmour DS, Pflugfelder G, Wang JC, Lis JT (1986) Topoisomerase I interacts with transcribed regions in Drosophila cells. Cell 44:401–407PubMedCrossRefGoogle Scholar
  46. Girod P-A and Mermod N (2003) Use of scaffold/matrix attachment regions for protein production. Gene Transfer and Expression in Mammalian cells. In S.C. Makrides (ed.), Elsevier Science pp. 359–379Google Scholar
  47. Girod P-A, Zahn-Zabal M, Mermod N (2005) Use of the chicken lysozyme 5′ matrix attachment region to generate high producer CHO cell lines. Biotechnol Bioeng 91:1–11PubMedCrossRefGoogle Scholar
  48. Girod P-A, Nguyen DQ, Calabrese D, Puttini S, Grandjean M, Martinet D, Regamey A, Saugy D, Beckmann JS, Bucher P, Mermod N (2007) Genome-wide prediction of matrix attachment regions that increase gene expression in mammalian cells. Nat Methods 4:747–753PubMedCrossRefGoogle Scholar
  49. Grewal SIS, Moazed D (2003) Heterochromatin and epigenetic control of gene expression. Science 301:798–802PubMedCrossRefGoogle Scholar
  50. Gutierrez-Adan A, Pintado B (2000) Effect of flanking matrix attachment regions on the expression of microinjected transgenes during preimplantation development of mouse embryos. Transgenic Res 9:81–89PubMedCrossRefGoogle Scholar
  51. Han HJ, Russo J, Kohwi Y, Kohwi-Shigematsu T (2008) SATB1 reprograms gene expression to promote breast tumor growth and metastasis. Nature 452:187–193PubMedCrossRefGoogle Scholar
  52. Hart CM, Laemmli UK (1998) Facilitation of chromatin dynamics by SARs. Curr Opin Genet Dev 8:519–525PubMedCrossRefGoogle Scholar
  53. Henikoff S (1996) Dosage-dependent modification of position-effect variegation in Drosophila. Bioessays 18:401–409PubMedCrossRefGoogle Scholar
  54. Herrscher RF, Kaplan MH, Lelsz DL, Das C, Scheuermann R, Tucker PW (1995) The immunoglobulin heavy-chain matrix-associating regions are bound by Bright: a B cell-specific trans-activator that describes a new DNA-binding protein family. Genes Dev 9:3067–3082PubMedCrossRefGoogle Scholar
  55. Homberger HP (1989) Bent DNA is a structural feature of scaffold-attached regions in Drosophila melanogaster interphase nuclei. Chromosoma 98:99–104PubMedCrossRefGoogle Scholar
  56. Iarovaia OV, Shkumatov P, Razin SV (2004) Breakpoint cluster regions of the AML-1 and ETO genes contain MAR elements and are preferentially associated with the nuclear matrix in proliferating HEL cells. J Cell Sci 117:4583–4590PubMedCrossRefGoogle Scholar
  57. John S, Reeves RB, Lin JX, Child R, Leiden JM, Thompson CB, Leonard WJ (1995) Regulation of cell-type-specific interleukin-2 receptor alpha-chain gene expression: potential role of physical interactions between Elf-1, HMG-I(Y), and NF-kappa B family proteins. Mol Cell Biol 15:1786–1796PubMedGoogle Scholar
  58. Johnson CN, Levy LS (2005) Matrix attachment regions as targets for retroviral integration. Virol J 2:68–77PubMedCrossRefGoogle Scholar
  59. Jun SC, Kim MS, Hong HJ, Lee GM (2006) Limitations to the development of humanized antibody producing Chinese hamster ovary cells using glutamine synthetase-mediated gene amplification. Biotechnol Prog 22:770–780PubMedCrossRefGoogle Scholar
  60. Kaffer CR, Srivastava M, Park KY, Ives E, Hsieh S, Batlle J, Grinberg A, Huang SP, Pfeifer K (2000) A transcriptional insulator at the imprinted H19/Igf2 locus. Genes Dev 14:1908–1919PubMedGoogle Scholar
  61. Kalos M, Fournier REK (1995) Position-independent transgene expression mediated by boundary elements from the apolipoprotein B chromatin domain. Mol Cell Biol 15:198–207PubMedGoogle Scholar
  62. Kamiya H, Fukunaga S, Ohyama T, Harashima H (2007) The location of the left-handedly curved DNA sequence affects exogenous DNA expression in vivo. Arch Biochem Biophys 461:7–12PubMedCrossRefGoogle Scholar
  63. Kim SJ, Lee GM (1999) Cytogenetic analysis of chimeric antibody-producing CHO cell sin the course of dihydrofolate reductase-mediated gene amplification and their stability in the absence of selective pressure. Biotechnol Bioeng 64:741–749PubMedCrossRefGoogle Scholar
  64. Kim SJ, Chun JR, Hong HJ, Lee GM (1998) Characterization of chimeric antibody producing CHO cells in the course of dihydrofolate reductase-mediated gene amplification and their stability in the absence of selective pressure. Biotechnol Bioeng 58:73–84PubMedCrossRefGoogle Scholar
  65. Kim NS, Kim SJ, Lee GM (1998) Clonal variation within dihydrofolate reductase-mediate gene amplified Chinese hamster ovary cells: stability in the absence of selective pressure. Biotech Bioeng 60:679–88CrossRefGoogle Scholar
  66. Kim NS, Byun TH, Lee GM (2001) Key determinants in the occurrence of clonal variation in humanized antibody expression of CHO cells during dihydrofolate reductase mediated gene amplification. Biotechnol Prog 17:69–75PubMedCrossRefGoogle Scholar
  67. Kim JM, Kim JS, Park DH, Kang HS, Yoon J, Baek K, Yoon Y (2004) Improved recombinant gene expression in CHO cells using matrix attachment regions. Biotechnol J 107:95–105CrossRefGoogle Scholar
  68. Kim JD, Yoon Y, Hwang HY, Park JS, SYu J Lee, Baek K, Yoon J (2005a) Efficient selection of stable Chinese hamster ovary (CHO) cell lines for expression of recombinant proteins by using human β-interferon SAR element. Biotechnol Prog 21:933–937PubMedCrossRefGoogle Scholar
  69. Kim TH, Barrera LO, Zheng M, Qu C, Singer MA, Richmond TA, Wu Y, Green RD, Ren B (2005b) A high-resolution map of active promoters in the human genome. Nature 436:876–880PubMedCrossRefGoogle Scholar
  70. Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B (2007) Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128:1231–1245PubMedCrossRefGoogle Scholar
  71. Klehr D, Maass K, Bode J (1991) Scaffold-attached regions from the human interferon beta domain can be used to enhance the stable expression of genes under the control of various promoters? Biochemistry 30:1264–1270PubMedCrossRefGoogle Scholar
  72. Klenova EM, Nicolas RH, Paterson HF, Carne AF, Heath CM, Goodwin GH, Neiman PE, Lobanenkov VV (1993) CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol 13:7612–7624PubMedGoogle Scholar
  73. Kohwi-Shigematsu T, deBelle I, Dickinson LA, Galande S, Kohwi Y (1998) Identification of base-unpairing region-binding proteins and characterization of their in vivo binding sequences. Methods Cell Biol 53:323–354PubMedCrossRefGoogle Scholar
  74. Kramer JA, Krawetz SA (1995) Matrix-associated regions in haploid expressed domains. Mamm Genome 6:677–679PubMedCrossRefGoogle Scholar
  75. Kumar PP, Purbey PK, Ravi DS, Mitra D, Galande S (2005) Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells. Mol Cell Biol 25:1620–1633PubMedCrossRefGoogle Scholar
  76. Kumar PP, Purbey PK, Sinha CK, Notani D, Limaye A, Jayani RS, Galande S (2006) Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo. Mol Cell 22:231–243CrossRefGoogle Scholar
  77. Kumar PP, Bischof O, Purbey PK, Notani D, Urlaub H, Dejean A, Galande S (2007) Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus. Nat Cell Biol 9:45–56PubMedCrossRefGoogle Scholar
  78. Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, Lobanenkov V, Reik W, Ohlsson R (2006) CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci USA 103:10684–10689PubMedCrossRefGoogle Scholar
  79. Kwaks THJ, Otte AP (2006) Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells. Trends Biotechnol 24:127–142CrossRefGoogle Scholar
  80. Labrador M, Corces VG (2002) Setting the boundaries of chromatin domains and nuclear organization. Cell 111:151–154PubMedCrossRefGoogle Scholar
  81. Landsman D, Bustin M (1993) A signature for the HMG-1 box DNA-binding proteins. Bioessays 15:539–546PubMedCrossRefGoogle Scholar
  82. Liebich I, Bode J, Reuter I, Wingender E (2002) Evaluation of sequence motifs found in scaffold/matrix-attached regions (S/MARs). Nucleic Acids Res 30:3433–3442PubMedCrossRefGoogle Scholar
  83. Ling JQ, Li T, Hu JF, Vu TH, Chen HL, Qiu XW, Cherry AM, Hoffman AR (2006) CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science 312:269–272PubMedCrossRefGoogle Scholar
  84. Liu WM, Guerra-Vladusic FK, Kurakata S, Lupu R, Kohwi-Shigematsu T (1999) HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its increased expression is directly linked to metastatic breast cancer phenotype. Cancer Res 59:5695–5703PubMedGoogle Scholar
  85. Maher JF, Nathans D (1996) Multivalent DNA-binding properties of the HMG-1 proteins. Proc Natl Acad Sci USA 93:6716–6720PubMedCrossRefGoogle Scholar
  86. Matzke M, Matzke A, Kooter J (2001) RNA: guiding gene silencing. Science 293:1080–1083PubMedCrossRefGoogle Scholar
  87. Melton DW, Brennand J, Ledbetter DH, Konecki DS, Chinault AC, Caskey CT (1982) Phenotypic reversion at the hprt locus as a consequence of gene amplification. In: Schimke RT (ed) Gene Amplification. Cold Spring Harbor Laboratory, New York, pp 59–65Google Scholar
  88. Morris K (2008) RNA-mediated transcriptional gene silencing in human cells. Curr Top Microbiol Immunol 320:211–214PubMedCrossRefGoogle Scholar
  89. Nishikawa J, Amano M, Fukue Y, Tanaka S, Kishi H, Hirota Y, Yoda K, Ohyama T (2003) Left-handedly curved DNA regulates accessibility to cis-DNA elements in chromatin. Nucleic Acids Res 31:6651–6662PubMedCrossRefGoogle Scholar
  90. Nowak W, Gawlowska M, Jarmolowski A, Augustyniak J (2001) Effect of nuclear matrix attachment regions on transgene expression in tobacco plants. Acta Biochim Pol 48:637–646PubMedGoogle Scholar
  91. Oh SJ, Jeong JS, Kim EH, Yi NR, Yi SI, Jang IC, Kim YS, Suh SC, Nahm BH, Kim JK (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 24:145–154PubMedCrossRefGoogle Scholar
  92. Ostermeier GC, Liu Z et al (2003) Nuclear matrix association of the human beta-globin locus utilizing a novel approach to quantitative real-time PCR. Nucleic Acids Res 31(12):3257–3266PubMedCrossRefGoogle Scholar
  93. Pankiewicz R, Karlen Y, Imhof M, Mermod N (2005) Reversal of the silencing of tetracycline-controlled genes requires the coordinate action of distinctly-acting transcription factors. J Gene Med 7:117–132PubMedCrossRefGoogle Scholar
  94. Park F, Kay MA (2001) Modified HIV-1 based lentiviral vectors have an effect on viral transduction efficiency and gene expression in vitro and in vivo. Mol Ther 4:164–173PubMedCrossRefGoogle Scholar
  95. Phi-Van L, Strätling WH (1996) Dissection of the ability of the chicken lysozyme gene 50 matrix attachment region to stimulate transgene expression and to dampen position effects. Biochemistry 35:10735–10742PubMedCrossRefGoogle Scholar
  96. Recillas-Targa F, Pikaart MJ, Burgess-Beusse B, Bell AC, Litt MD, West AG, Gaszner M, Felsenfeld G (2002) Position-effect protection and enhancer blocking by the chicken β-globin insulator are separable activities. Proc Natl Acad Sci USA 99:6883–6888PubMedCrossRefGoogle Scholar
  97. Reeves R, Edberg DD, Li Y (2001) Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol 21:575–594PubMedCrossRefGoogle Scholar
  98. Rincon-Arano H, Furlan-Magaril M, Recillas-Targa F (2007) Protection against telomeric position effects by the chicken cHS4 beta-globin insulator. Proc Natl Acad Sci USA 104:14044–14049PubMedCrossRefGoogle Scholar
  99. Robertson G, Garrick D, Wu W, Kearns M, Martin D, Whitelaw E (1995) Position-dependent variegation of globin transgene expression in mice. Proc Natl Acad Sci USA 92:5371–5375PubMedCrossRefGoogle Scholar
  100. Robins DM, Ripley S, Henderson AS, Axel R (1981) Transforming DNA integrates into the host chromosome. Cell 23:29–39PubMedCrossRefGoogle Scholar
  101. Romig H, Fackelmayer FO, Renz A, Ramsperger U, Richter A (1992) Characterization of SAF-A, a novel nuclear DNA binding protein from HeLa cells with high affinity for nuclear matrix/scaffold attachment DNA elements. EMBO J 11:3431–3440PubMedGoogle Scholar
  102. Saitoh Y, Laemmli UK (1993) From the chromosomal loops and the scaffold to the classic bands of metaphase chromosomes. Cold Spring Harb Symp Quant Biol 58:755–765PubMedGoogle Scholar
  103. Saitoh Y, Laemmli UK (1994) Metaphase chromosome structure: bands arise from a differential folding path of the highly AT-rich scaffold. Cell 76:609–622PubMedCrossRefGoogle Scholar
  104. Schubeler D, Mielke C, Maass K, Bode J (1996) Scaffold/matrix-attached regions act upon transcription in a context-dependent manner. Biochemistry 35:11160–11169PubMedCrossRefGoogle Scholar
  105. Selker EU (1999) Gene silencing: repeats that count. Cell 97:157–160PubMedCrossRefGoogle Scholar
  106. Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, Manfioletti G, Giancotti V (2004) Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer. FEBS Lett 574:1–8PubMedCrossRefGoogle Scholar
  107. Sjakste NR, Sjakste TG (2001) Use of scaffold/matrix-attachment regions for protein production. Mol Biol 35:627–635CrossRefGoogle Scholar
  108. Solomon MJ, Strauss F, Varshavsky A (1986) A mammalian high mobility group protein recognizes any stretch of six A.T base pairs in duplex DNA. Proc Natl Acad Sci USA 83:1276–1280PubMedCrossRefGoogle Scholar
  109. Stief A, Winter DM, Strätling WH, Sippel AE (1989) A nuclear DNA attachment element mediates elevated and position-independent gene activity. Nature 341:343–345PubMedCrossRefGoogle Scholar
  110. Strutzenberger K, Borth N, Kunert R, Steinfellner W, Katinger H (1999) Changes during subclone development, ageing of human antibody- producing recombinant CHO cells. J Biotechnol 69:215–226PubMedCrossRefGoogle Scholar
  111. Sumida N, Nishikawa J, Kishi H, Amano M, Furuya T, Sonobe H, Ohyama T (2006) A designed curved DNA segment that is a remarkable activator of eukaryotic transcription. FEBS J 273:5691–5702PubMedCrossRefGoogle Scholar
  112. Thanos D, Maniatis T (1992) The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell 71:777–789PubMedCrossRefGoogle Scholar
  113. Thomas KR, Folger KR, Capecchi MR (1986) High frequency targeting of genes to specific sites in the mammalian genome. Cell 44:419–428PubMedCrossRefGoogle Scholar
  114. Thompson EM, Christians E, Stinnakre MG, Renard JP (1994) Scaffold attachment regions stimulate HSP70.1 expression in mouse preimplantation embryos but not in differentiated tissues. Mol Cell Biol 14:4694–4703PubMedGoogle Scholar
  115. Thorvaldsen JL, Duran KL, Bartolomei MS (1998) Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev 12:3693–3702PubMedCrossRefGoogle Scholar
  116. Torrungruang K, Alvarez M, Shah R, Onyia JE, Rhodes SJ, Bidwell JP (2002) DNA binding and gene activation properties of the Nmp4 nuclear matrix transcription factors. J Biol Chem 277:16153–16159PubMedCrossRefGoogle Scholar
  117. Varghese J, Alves W, Brill BJ, Wallace M, Calabrese D, Regamey A, Girod PA. (2008) Rapid development of high-performance, stable mammalian cell lines for improved clinical development. Bioprocess J 7:30–36Google Scholar
  118. Volfson D et al (2006) Origins of extrinsic variability in eukaryotic gene expression. Nature 439:861–864PubMedCrossRefGoogle Scholar
  119. Wakimoto BT (1998) Beyond the nucleosome: epigenetic aspects of position-effect variegation in Drosophila. Cell 93:321–324PubMedCrossRefGoogle Scholar
  120. Wang T, Xue L, Hou W, Yang B, Chai Y, Ji X, Wang Y (2007) Increased expression of transgene in stably transformed cells of Dunaliella salina by matrix attachment regions. Appl Microbiol Biotechnol 76:651–657PubMedCrossRefGoogle Scholar
  121. West A, Gaszner M, Felsenfeld G (2002) Insulators: many functions, many mechanisms. Genes Dev 16:271–288PubMedCrossRefGoogle Scholar
  122. Wilson C, Bellen HJ, Gehring WJ (1990) Position effects on eukaryotic gene expression. Annu Rev Cell Biol 6:679–714PubMedCrossRefGoogle Scholar
  123. Woodcock CL, Dimitrov S (2001) Higher-order structure of chromatin and chromosomes. Curr Opin Genet Dev 11:130–5PubMedCrossRefGoogle Scholar
  124. Xu Y, Davidson L, Alt FW, Baltimore D (1996) Deletion of the Ig kappa light chain intronic enhancer/matrix attachment region impairs but does not abolish V kappa J kappa rearrangement. Immunity 4:377–385PubMedCrossRefGoogle Scholar
  125. Yamasaki K, Akiba T, Yamasak T, Harata K (2007) Structural basis for recognition of the matrix attachment region of DNA by transcription factor SATB1. Nucleic Acids Res 35:5073–5084PubMedCrossRefGoogle Scholar
  126. Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T (2002) SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 419:641–645PubMedCrossRefGoogle Scholar
  127. Yoshikawa T, Nakanishi F, Ogura Y, Oi D, Omasa T, Katakura Y, Kishimoto M, Suga K (2000) Amplified gene location in chromosomal DNA affected recombinant protein production and stability of amplified genes. Biotechnol Progr 16:710–715CrossRefGoogle Scholar
  128. Zahn-Zabal M, Kobr M, Girod PA, Imhof M, Chatellard P, de Jesus M, Wurm F, Mermod N (2001) Development of stable cell lines for production or regulated expression using matrix attachment regions. J Biotechnol 87:29–42PubMedCrossRefGoogle Scholar
  129. Zhao K, Kas E, Gonzalez E, Laemmli UK (1993) SAR-dependent mobilization of histone H1 by HMG-I/Y in vitro: HMG-I/Y is enriched in H1-depleted chromatin. Embo J 12:3237–3247PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Cori Gorman
    • 1
    • 2
  • Salina Arope
    • 3
  • Mélanie Grandjean
    • 3
  • Pierre-Alain Girod
    • 1
  • Nicolas Mermod
    • 3
  1. 1.Selexis SAPlan-les-OuatesSwitzerland
  2. 2.DNA Gateway International, Inc.San FranciscoUSA
  3. 3.Laboratory of Molecular BiotechnologyUniversity of LausanneLausanneSwitzerland

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