Epigenetic regulatory elements: recent advances in understanding their mode of action and use for recombinant protein production in mammalian cells
Abstract
Successful generation of high producing cell lines requires the generation of cell clones expressing the recombinant protein at high levels and the characterization of the clones' ability to maintain stable expression levels. The use of cis‐acting epigenetic regulatory elements that improve this otherwise long and uncertain process has revolutionized recombinant protein production. Here we review and discuss new insights into the molecular mode of action of the matrix attachment regions (MARs) and ubiquitously‐acting chromatin opening elements (UCOEs), i.e. cis‐acting elements, and how these elements are being used to improve recombinant protein production. These elements can help maintain the chromatin environment of the transgene genomic integration locus in a transcriptionally favorable state, which increases the numbers of positive clones and the transgene expression levels. Moreover, the high producing clones tend to be more stable in long‐term cultures even in the absence of selection pressure. Therefore, by increasing the probability of isolating a high producing clone, as well as by increasing transcription efficiency and stability, these elements can significantly reduce the time and cost required for producing large quantities of recombinant proteins.
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Conflicting results in the literature have led to the conclusion that MAR activity could be sequence-specific and is influenced by specific vector configuration.
“However, conflicting results in the literature have led to the conclusion that MAR activity could be sequence-specific and is influenced by specific vector configuration (Harraghy et al., 2015).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Harraghy et al., 2015
Including MAR elements in expression vectors for recombinant proteins could significantly improve expression levels.
“Many reports have shown that including these MAR elements in expression vectors for recombinant proteins could significantly improve the expression levels (for an extensive review see (Harraghy et al., 2015)).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Harraghy et al., 2015
Development of bioinformatic tools capable to predict the outcome of MAR sequences helped to improve MAR elements.
“In recent years, development of bioinformatic tools capable to predict the outcome of MAR sequences helped to improve MAR elements (Girod et al., 2007;Harraghy et al., 2012Harraghy et al., , 2015)).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Harraghy et al., 2015
Because most epigenetic elements are composed of nucleosome depleted regions, they could contribute to inhibiting the propagation of an inactive chromatin state surrounding the transgene, serving as genetic boundaries.
“Since most of these elements are composed of nucleosome depleted regions, this could also contribute to the inhibition of the propagation of an inactive chromatin state surrounding the transgene, serving as genetic boundaries (Arope et al., 2013;Harraghy et al., 2015).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Harraghy et al., 2015
Inclusion of epigenetic elements can help increase the expression level of biotherapeutics.
“Inclusion of these various epigenetic elements not only can help to increase the expression level of biotherapeutics, but can also increase the number of clones that have integrated the transgene with a more defined copy number of transgene per cell, thus accelerating the selection process (Grandjean et al., 2011;Harraghy et al., 2015).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Harraghy et al., 2015
Inclusion of epigenetic elements can increase the number of clones that have integrated the transgene with a more defined copy number of transgene per cell, thus accelerating the selection process.
“Inclusion of these various epigenetic elements not only can help to increase the expression level of biotherapeutics, but can also increase the number of clones that have integrated the transgene with a more defined copy number of transgene per cell, thus accelerating the selection process (Grandjean et al., 2011;Harraghy et al., 2015).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Harraghy et al., 2015
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- Authors
- Harraghy, N., Calabrese, D., Fisch, I., Girod, P., LeFourn, V., Regamey, A., & Mermod, N.
- Affiliations
- University of Lausanne (CH)
- Corresponding author
- Mermod, Nicolas
- Venue
- Biotechnology Journal
- Publisher
- Wiley
- Published
- 2015-06-23
- Volume
- 10
- Issue
- 7
- Pages
- 967-978
- ISSN
- 1860-6768 (ISSN-L)
- 1860-7314
- OpenAlex
- W1948393835
- Cited by
- 32
- References
- 96
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 2
- FWCI
- 0.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biotechnology Journal (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Commission for Technology and Innovation of the Swiss Confederation, and Selexis SA (8793.1 BTS-LS and 13939.1 PFLS-LS)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- matrix attachment regions, cis-regulatory elements, recombinant protein expression, mammalian cell expression systems, transgene stability, chromatin environment
- MeSH terms
- Animals, Chromatin, Cricetulus, Cricetinae, Recombinant Proteins, Regulatory Sequences, Nucleic Acid, CHO Cells, Transgenes, Gene Silencing, Epigenesis, Genetic, Matrix Attachment Regions
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