Epigenetic regulatory elements: Recent advances in understanding their mode of action and use for recombinant protein production in mammalian cells

Biotechnology Journal

Volumn 10, Issue 7, 2015, Pages 967-978

  Harraghy, Niamh ^a,b   Calabrese, David ^a   Fisch, Igor ^a   Girod, Pierre Alain ^a   Lefourn, Valérie ^a   Regamey, Alexandre ^a   Mermod, Nicolas ^b  

^a Selexis SA   (Switzerland)

^b UNIVERSITY OF LAUSANNE   (Switzerland)

Author keywords

Epigenetics; Matrix attachment region; Recombinant protein production; Transgene silencing; Ubiquitously acting chromatin opening element

Indexed keywords

CELL CULTURE; CHROMOSOMES; CLONE CELLS; MAMMALS; PROTEINS; TOBACCO;

EPIGENETICS; MATRIX ATTACHMENT REGION; RECOMBINANT PROTEIN PRODUCTIONS; TRANSGENE SILENCING; UBIQUITOUSLY-ACTING CHROMATIN OPENING ELEMENT;

RECOMBINANT PROTEINS;

CIS ACTING ELEMENT; DNA; RECOMBINANT PROTEIN; CHROMATIN;

CHROMATIN; CLONE; COPY NUMBER VARIATION; DNA METHYLATION; EPIGENETICS; GENE AMPLIFICATION; GENE EXPRESSION; GENE SILENCING; GENE THERAPY; GENETIC TRANSCRIPTION; INSULATOR ELEMENT; MAMMAL CELL; MATRIX ATTACHMENT REGION; NONHUMAN; PRIORITY JOURNAL; PROBABILITY; PROTEIN EXPRESSION; REGULATORY SEQUENCE; REVIEW; TRANSGENE; ANIMAL; BIOSYNTHESIS; CHO CELL LINE; CRICETULUS; GENETIC EPIGENESIS; GENETICS; HAMSTER;

MAMMALIA;

ANIMALS; CHO CELLS; CHROMATIN; CRICETINAE; CRICETULUS; EPIGENESIS, GENETIC; GENE SILENCING; MATRIX ATTACHMENT REGIONS; RECOMBINANT PROTEINS; REGULATORY SEQUENCES, NUCLEIC ACID; TRANSGENES;

EID: 84935737610     PISSN: 18606768     EISSN: 18607314     Source Type: Journal    
DOI: 10.1002/biot.201400649     Document Type: Review

References (95)

1. Palazzoli, F., Bire, S., Bigot, Y., Bonnin-Rouleux, F., Landscape of chromatin control element patents: Positioning effects in pharmaceutical bioproduction. Nat. Biotech. 2011, 29, 593-597.
2. Linnemann, A. K., Krawetz, S. A., Maintenance of a functional higher order chromatin structure: the role of the nuclear matrix in normal and disease states. Genes Ther. Mol. Biol. 2009, 13, 231-243.
3. Bode, J., Benham, C., Knopp, A., Mielke, C., Transcriptional augmentation: Modulation of gene expression by scaffold/matrix-attached regions (S/MAR elements). Crit. Rev. Eukaryot. Gene Expr. 2000, 10, 73-90.
4. Bode, J., Goetze, S., Heng, H., Krawetz, S. A., Benham, C., From DNA structure to gene expression: Mediators of nuclear compartmentalization and dynamics. Chromosome Res. 2003, 11, 435-445.
5. Girod, P. A., Mermod, N., Use of scaffold/matrix attachement regions for protein production. In: Makrides, S. C. (Ed.) New Comprehensive Biochemistry, Elsevier, Amsterdam2003, pp. 359-379.
6. Gorman, C., Arope, S., Grandjean, M., Girod, P. A., Mermod, N., Use of MAR elements to increase the production of recombinant proteins. Cell Engineering 2009, 6, 1-32.
7. Kwaks, T. H., Otte, A. P., Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells. Trends Biotechnol. 2006, 24, 137-142.
8. Dean, A., In the loop: Long range chromatin interactions and gene regulation. Brief. Funct. Genomics 2011, 10, 3-10.
9. Giles, K. E., Gowher, H., Ghirlando, R., Jin, C., Felsenfeld, G., Chromatin boundaries, insulators, and long-range interactions in the nucleus. Cold Spring Harb. Symp. Quant. Biol. 2010, 75, 79-85.
10. Razin, S. V., Farrell, C. M., Recillas-Targa, F., Genomic domains and regulatory elements operating at the domain level. Int. Rev. Cytol. 2003, 226, 63-125.
11. Bode, J., Maass, K., Chromatin domain surrounding the human interferon-beta gene as defined by scaffold-attached regions. Biochemistry 1988, 27, 4706-4711.
12. Girod, P. A., Zahn-Zabal, M., Mermod, N., Use of the chicken lysozyme 5' matrix attachment region to generate high producer CHO cell lines. Biotechnol. Bioeng. 2005, 91, 1-11.
13. Loc, P. V., Stratling, W. H., The matrix attachment regions of the chicken lysozyme gene co-map with the boundaries of the chromatin domain. EMBO J. 1988, 7, 655-664.
14. Phi-Van, L., von Kries, J. P., Ostertag, W., Stratling, W. H., The chicken lysozyme 5' matrix attachment region increases transcription from a heterologous promoter in heterologous cells and dampens position effects on the expression of transfected genes. Mol. Cell. Biol. 1990, 10, 2302-2307.
15. Yu, J., Bock, J. H., Slightom, J. L., Villeponteau, B., A 5' beta-globin matrix-attachment region and the polyoma enhancer together confer position-independent transcription. Gene 1994, 139, 139-145.
16. Klehr, D., Maass, K., Bode, J., 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 1991, 30, 1264-1270.
17. Harraghy, N., Gaussin, A., Mermod, N., Sustained transgene expression using MAR elements. Curr. Gene Ther. 2008, 8, 353-366.
18. Hagedorn, C., Wong, S. P., Harbottle, R., Lipps, H. J., Scaffold/matrix attached region-based nonviral episomal vectors. Hum. Gene Ther. 2011, 22, 915-923.
19. Harraghy, N., Buceta, M., Regamey, A., Girod, P. A., Mermod, N., Using matrix attachment regions to improve recombinant protein production. Methods Mol. Biol. 2012, 801, 93-110.
20. Girod, P. A., Nguyen, D. Q., Calabrese, D., Puttini, S. et al., Genome-wide prediction of matrix attachment regions that increase gene expression in mammalian cells. Nat. Methods 2007, 4, 747-753.
21. She, X., Rohl, C. A., Castle, J. C., Kulkarni, A. V. et al., Definition, conservation and epigenetics of housekeeping and tissue-enriched genes. BMC Genomics 2009, 10, 269.
22. Benton, T., Chen, T., McEntee, M., Fox, B. et al., The use of UCOE vectors in combination with a preadapted serum free, suspension cell line allows for rapid production of large quantities of protein. Cytotechnology 2002, 38, 43-46.
23. Zhang, F., Frost, A. R., Blundell, M. P., Bales, O. et al., A Ubiquitous Chromatin Opening Element (UCOE) confers resistance to DNA methylation-mediated silencing of lentiviral vectors. Mol. Ther. 2010, 18, 1640-1649.
24. Sautter, K., Enenkel, B., Selection of high-producing CHO cells using NPT selection marker with reduced enzyme activity. Biotechnol. Bioeng. 2005, 89, 530-538.
25. van Blokland, H. J., Kwaks, T. H., Sewalt, R. G., Verhees, J. A. et al., A novel, high stringency selection system allows screening of few clones for high protein expression. J. Biotechnol. 2007, 128, 237-245.
26. van Blokland, H. J. M., Hoeksema, F., Siep, M., Otte, A. P., Verhees, J. A., Methods to create a stringent selection system for mammalian cell lines. Cytotechnology 2011, 63, 371-384.
27. Kwaks, T. H., Barnett, P., Hemrika, W., Siersma, T. et al., Identification of anti-repressor elements that confer high and stable protein production in mammalian cells. Nat. Biotechnol. 2003, 21, 553-558.
28. Hoeksema, F., Van Blokland, R., Siep, M., Hamer, K. et al., The use of a stringent selection system allows the identification of DNA elements that augment gene expression. Mol. Biotechnol. 2011, 48, 19-29.
29. Hoeksema, F., Hamer, K., Siep, M., Verhees, J. A., Otte, A. P., Placing the RPL32 promoter upstream of a second promoter results in a strongly increased number of stably transfected mammalian cell lines that display high protein expression levels. Biotechnol. Research Int. 2011, 2011, 492875.
30. Chusainow, J., Yang, Y. S., Yeo, J. H., Toh, P. C. et al., A study of monoclonal antibody-producing CHO cell lines: What makes a stable high producer? Biotechnol. Bioeng. 2009, 102, 1182-1196.
31. Schlatter, S., Stansfield, S. H., Dinnis, D. M., Racher, A. J. et al., On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells. Biotechnol. Prog. 2005, 21, 122-133.
32. Grandjean, M., Girod, P. A., Calabrese, D., Kostyrko, K. et al., High-level transgene expression by homologous recombination-mediated gene transfer. Nucleic Acids Res. 2011, 39, e104.
33. Araki, Y., Hamafuji, T., Noguchi, C., Shimizu, N., Efficient recombinant production in mammalian cells using a novel IR/MAR gene amplification method. PLoS One 2012, 7, e41787.
34. Okada, N., Shimizu, N., Dissection of the beta-globin replication-initiation region reveals specific requirements for replicator elements during gene amplification. PLoS One 2013, 8, e77350.
35. Tanaka, S. S., Mitsuda, S. H., Shimizu, N., How a replication origin and matrix attachment region accelerate gene amplification under replication stress in mammalian cells. PLoS One 2014, 9, e103439.
36. Noguchi, C., Araki, Y., Miki, D., Shimizu, N., Fusion of the Dhfr/Mtx and IR/MAR gene amplification methods produces a rapid and efficient method for stable recombinant protein production. PLoS One 2012, 7.
37. Barnes, L. M., Bentley, C. M., Dickson, A. J., Stability of protein production from recombinant mammalian cells. Biotechnol. Bioeng. 2003, 81, 631-639.
38. Pilbrough, W., Munro, T. P., Gray, P., Intraclonal protein expression heterogeneity in recombinant CHO cells. PLoS One 2009, 4, e8432.
39. Nair, A. R., Jinger, X., Hermiston, T. W., Effect of different UCOE-promoter combinations in creation of engineered cell lines for the production of Factor VIII. BMC Res. Notes 2011, 4, 178.
40. Harraghy, N., Regamey, A., Girod, P. A., Mermod, N., Identification of a potent MAR element from the mouse genome and assessment of its activity in stable and transient transfections. J. Biotechnol. 2011, 154, 11-20.
41. Williams, S., Mustoe, T., Mulcahy, T., Griffiths, M. et al., 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. 2005, 5, 17.
42. Galbete, J. L., Buceta, M., Mermod, N., MAR elements regulate the probability of epigenetic switching between active and inactive gene expression. Mol. Biosyst. 2009, 5, 143-150.
43. Arope, S., Harraghy, N., Pjanic, M., Mermod, N., Molecular characterization of a human matrix attachment region epigenetic regulator. PLoS One 2013, 8, e79262.
44. Majocchi, S., Aritonovska, E., Mermod, N., Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes. Nucleic Acids Res. 2014, 42, 193-204.
45. Ley, D., Harraghy, N., Le Fourn, V., Bire, S. et al., MAR elements and transposons for improved transgene integration and expression. PLoS One 2013, 8, e62784.
46. Antoniou, M., Harland, L., Mustoe, T., Williams, S. et al., Transgenes encompassing dual-promoter CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing. Genomics 2003, 82, 269-279.
47. Wang, F., Wang, T. Y., Tang, Y. Y., Zhang, J. H., Yang, X. J., Different matrix attachment regions flanking a transgene effectively enhance gene expression in stably transfected Chinese hamster ovary cells. Gene 2012, 500, 59-62.
48. Chang, M., Liu, R., Jin, Q., Liu, Y., Wang, X., Scaffold/matrix attachment regions from CHO cell chromosome enhanced the stable transfection efficiency and the expression of transgene in CHO cells. Biotechnol. App. Biochem. 2014, 61, 510-516.
49. Zhang, J. H., Wang, X. Y., Wang, T. Y., Wang, F. et al., Distance effect of matrix attachment regions on transgene expression in stably transfected Chinese hamster ovary cells. Biotechnol. Lett. 2014, 36, 1937-1943.
50. Kim, J. M., Kim, J. S., Park, D. H., Kang, H. S. et al., Improved recombinant gene expression in CHO cells using matrix attachment regions. J. Biotechnol. 2004, 107, 95-105.
51. Oh, S. J., Jeong, J. S., Kim, E. H., Yi, N. R. et al., 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. 2005, 24, 145-154.
52. Zhang, F., Thornhill, S. I., Howe, S. J., Ulaganathan, M. et al., Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells. Blood 2007, 110, 1448-1457.
53. Stief, A., Winter, D. M., Stratling, W. H., Sippel, A. E., A nuclear DNA attachment element mediates elevated and position-independent gene activity. Nature 1989, 341, 343-345.
54. Jenuwein, T., Forrester, W. C., Fernández-Herrero, L. A., Laible, G. et al., Extension of chromatin accessibility by nuclear matrix attachment regions. Nature 1997, 385, 269-272.
55. Nayler, O., Strätling, W., Bourquin, J. P., Stagljar, I. et al., SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements. Nucleic Acids Res. 1998, 26, 3542-3549.
56. Durrin, L. K., Krontiris, T. G., The thymocyte-specific MAR binding protein, SATB1, interacts in vitro with a novel variant of DNA-directed RNA polymerase II, subunit 11. Genomics 2002, 79, 809-817.
57. Allen, M. L., Antoniou, M., Correlation of DNA methylation with histone modifications across the HNRPA2B1-CBX3 Ubiquitously-Acting Chromatin Open Element (UCOE). Epigenetics 2007, 2, 227-236.
58. Backliwal, G., Hildinger, M., Kuettel, I., Delegrange, F. et al., Valproic acid: A viable alternative to sodium butyrate for enhancing protein expression in mammalian cell cultures. Biotechnol. Bioeng. 2008, 101, 182-189.
59. Jiang, Z., Sharfstein, S. T., Sodium butyrate stimulates monoclonal antibody over-expression in CHO cells by improving gene accessibility. Biotechnol. Bioeng. 2008, 100, 189-194.
60. Wulhfard, S., Baldi, L., Hacker, D. L., Wurm, F., Valproic acid enhances recombinant mRNA and protein levels in transiently transfected Chinese hamster ovary cells. J. Biotechnol. 2010, 148, 128-132.
61. Bell, O., Tiwari, V. K., Thomä, N. H., Schübeler, D., Determinants and dynamics of genome accessibility. Nat. Rev. Genet. 2011, 12, 554-564.
62. Bode, J., Schlake, T., Rios-Ramirez, M., Mielke, C. et al., Scaffold/matrix-attached regions: structural properties creating transcriptionally active loci. Int. Rev. Cytol. 1995, 162A, 389-454.
63. Yang, Y., Mariati Chusainow, J., Yap, M. G., DNA methylation contributes to loss in productivity of monoclonal antibody-producing CHO cell lines. J. Biotechnol. 2010, 147, 180-185.
64. Kim, M., O'Callaghan, P. M., Droms, K. A., James, D. C., A mechanistic understanding of production instability in CHO cell lines expressing recombinant monoclonal antibodies. Biotechnol. Bioeng. 2011, 108, 2434-2446.
65. Appanah, R., Dickerson, D. R., Goyal, P., Groudine, M., Lorincz, M. C., An unmethylated 3' promoter-proximal region is required for efficient transcription initiation. PLoS Genet. 2007, 3, e27.
66. Kisseljova, N. P., Dmitriev, P., Katargin, A., Kim, E. et al., DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix. Eur. J. Hum. Genet. 2014, 22, 1117-1123.
67. Dang, Q., Auten, J., Plavec, I., Human beta interferon scaffold attachment region inhibits de novo methylation and confers long-term, copy number-dependent expression to a retroviral vector. J. Virol. 2000, 74, 2671-2678.
68. Rangasamy, D., An S/MAR-based L1 retrotransposition cassette mediates sustained levels of insertional mutagenesis without suffering from epigenetic silencing of DNA methylation. Epigenetics 2010, 5, 601-611.
69. Chiurazzi, P., Pomponi, M. G., Pietrobono, R., Bakker, C. E. et al., Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum. Mol. Genet. 1999, 8, 2317-2323.
70. Mutskov, V. J., Farrell, C. M., Wade, P. A., Wolffe, A. P., Felsenfeld, G., The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation. Genes Dev. 2002, 16, 1540-1554.
71. Mobius, W., Gerland, U., Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites. PLoS Comput. Biol. 2010, 6, e1000891.
72. West, A. G., Fraser, P., Remote control of gene transcription. Hum. Mol. Genet. 2005, 14, R101-111.
73. Linnemann, A. K., Platts, A. E., Doggett, N., Gluch, A. et al., Genomewide identification of nuclear matrix attachment regions: An analysis of methods. Biochem. Soc. T. 2007, 35, 612-617.
74. Linnemann, A. K., Krawetz, S. A., Silencing by nuclear matrix attachment distinguishes cell-type specificity: Association with increased proliferation capacity. Nucleic Acids Res. 2009, 37, 2779-2788.
75. Heng, H. H., Goetze, S., Ye, C. J., Liu, G. et al., Chromatin loops are selectively anchored using scaffold/matrix-attachment regions. J. Cell Sci. 2004, 117, 999-1008.
76. Ho, S. C., Mariati Yeo, J. H., Fang, S. G., Yang, Y., Impact of using different promoters and matrix attachment regions on recombinant protein expression level and stability in stably transfected CHO cells. Mol. Biotechnol. 2015, 57, 138-144.
77. Senigl, F., Plachy, J., Hejnar, J., The core element of a CpG island protects avian sarcoma and leukosis virus-derived vectors from transcriptional silencing. J. Virol. 2008, 82, 7818-7827.
78. Goetze, S., Baer, A., Winkelmann, S., Nehlsen, K. et al., Performance of genomic bordering elements at predefined genomic loci. Mol. Cell. Biol. 2005, 25, 2260-2272.
79. Hou, J. J. C., Hughes, B. S., Smede, M., Leung, K. M. et al., High-throughput ClonePix FL analysis of mAb-expressing clones using the UCOE expression system. N. Biotechnol. 2014, 31, 214-220.
80. Sieck, J. B., Budach, W. E., Suemeghy, Z., Leist, C. et al., Adaptation for survival: Phenotype and transcriptome response of CHO cells to elevated stress induced by agitation and sparging. J. Biotechnol. 2014, 189, 94-103.
81. Dhanasekharan, K., Berdugo-Davis, C., Liu, X., Richey, C. et al., Rapid development and scale-up through strategic partnership: Case study of an integrated approach to cell line and process development. Bioprocess Int. 2014, 12, 38-41.
82. Gim, J. A., Hong, C. P., Kim, D. S., Moon, J. W. et al., Genome-wide analysis of DNA methylation before and after exercise in the thoroughbred horse with MeDIP-Seq. Mol. Cells 2015, 38, 210-220.
83. Seo, J. Y., Park, Y. J., Yi, Y. A., Hwang, J. Y. et al., Epigenetics: General characteristics and implications for oral health. Restor. Dent. Endod. 2015, 40, 14-22.
84. Brezinsky, S. C., Chiang, G. G., Szilvasi, A., Mohan, S. et al., A simple method for enriching populations of transfected CHO cells for cells of higher specific productivity. J. Immunol. Methods 2003, 277, 141-155.
85. Gluch, A., Vidakovic, M., Bode, J., Scaffold/matrix attachment regions (S/MARs): Relevance for disease and therapy. Handb. Exp. Pharmacol. 2008, 186, 67-103.
86. Jiang, Z., Huang, Y., Sharfstein, S. T., Regulation of recombinant monoclonal antibody production in chinese hamster ovary cells: A comparative study of gene copy number, mRNA level, and protein expression. Biotechnol. Prog. 2006, 22, 313-318.
87. West, S., Proudfoot, N. J., Transcriptional termination enhances protein expression in human cells. Mol. Cell 2009, 33, 354-364.
88. Yang, Y., Ho, S. C., Yap, M. G., Mutated polyadenylation signals for controlling expression levels of multiple genes in mammalian cells. Biotechnol. Bioeng. 2009, 102, 1152-1160.
89. Ehrlich, M., Lacey, M., DNA methylation and differentiation: Silencing, upregulation and modulation of gene expression. Epigenomics 2013, 5, 553-568.
90. Kim, J. D., Yoon, Y., Hwang, H. Y., Park, J. S. et al., Efficient selection of stable Chinese hamster ovary (CHO) cell lines for expression of recombinant proteins by using human interferon beta SAR element. Biotechnol. Prog. 2005, 21, 933-937.
91. Piechaczek, C., Fetzer, C., Baiker, A., Bode, J., Lipps, H. J., A vector based on the SV40 origin of replication and chromosomal S/MARs replicates episomally in CHO cells. Nucleic Acids Res. 1999, 27, 426-428.
92. Tsutsui, K., Tsutsui, K., Okada, S., Watarai, S. et al., Identification and characterization of a nuclear scaffold protein that binds the matrix attachment region DNA. J. Biol. Chem. 1993, 268, 12886-12894.
93. Shimizu, N., Miura, Y., Sakamoto, Y., Tsutsui, K., Plasmids with a mammalian replication origin and a matrix attachment region initiate the event similar to gene amplification. Cancer Res. 2001, 61, 6987-6990.
94. Ye, J., Alvin, K., Latif, H., Hsu, A. et al., Rapid protein production using CHO stable transfection pools. Biotechnol. Prog. 2010, 26, 1431-1437.
95. Boscolo, S., Mion, F., Licciulli, M., Macor, P. et al., Simple scale-up of recombinant antibody production using an UCOE containing vector. Nat. Biotechnol. 2012, 29, 477-484.