ArticleBMC biotechnology2016
Mechanisms underlying epigenetic and transcriptional heterogeneity in Chinese hamster ovary (CHO) cell lines.
Article in BMC biotechnology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 62 citations in OpenAlex.
- Improving recombinant protein productivity in CHO cells via multi-omics data integration.Bioresources and bioprocessing · 2026Review
- Exploring CHO cell stability during prolonged passaging via eXplainable AI driven flux balance analysis.NPJ systems biology and applications · 2026Article
- Advancing recombinant protein production in CHO cells through metabolic engineering.Frontiers in bioengineering and biotechnology · 2026Review
- Reversing transgene silencing via targeted chromatin editing.bioRxiv : the preprint server for biology · 2025Article
- MemorySeq identifies heritable epigenetic phenotypes that initiate cell culture stress tolerance in CHO cells.iScience · 2025Article
- SETDB1 knockdown boosts recombinant protein in CHO cells via epigenetic transcriptional silencing.AMB Express · 2025Article
- From Cell Clones to Recombinant Protein Product Heterogeneity in Chinese Hamster Ovary Cell Systems.International journal of molecular sciences · 2025Review
- Barriers Composed of tRNA Genes Can Complement the Benefits of a Ubiquitous Chromatin Opening Element to Enhance Transgene Expression.Biotechnology journal · 2025Article
- Next-generation sequencing: A powerful multi-purpose tool in cell line development for biologics production.Computational and structural biotechnology journal · 2025Review
- Selective Recruitment of a Synthetic Histone Acetyltransferase Can Boost CHO Cell Productivity.Biotechnology journal · 2024Article
- The Role of Endoplasmic Reticulum Stress on Reducing Recombinant Protein Production in Mammalian Cells.Biochemical engineering journal · 2024Article
- A novel dual-epigenetic inhibitor enhances recombinant monoclonal antibody expression in CHO cells.Applied microbiology and biotechnology · 2024Article
- Long term culturing of CHO cells: phenotypic drift and quality attributes of the expressed monoclonal antibody.Biotechnology letters · 2023Article
- Use of ubiquitous chromatin opening elements (UCOE) as tools to maintain transgene expression in biotechnology.Computational and structural biotechnology journal · 2023Review
- Restoration of DNA repair mitigates genome instability and increases productivity of Chinese hamster ovary cells.Biotechnology and bioengineering · 2022Article
- Characterization of metabolic responses, genetic variations, and microsatellite instability in ammonia-stressed CHO cells grown in fed-batch cultures.BMC biotechnology · 2021Article
- Expression vector cassette engineering for recombinant therapeutic production in mammalian cell systems.Applied microbiology and biotechnology · 2020Review
- An efficient protein production system via gene amplification on a human artificial chromosome and the chromosome transfer to CHO cells.Scientific reports · 2019Article
- Increased mAb production in amplified CHO cell lines is associated with increased interaction of CREB1 with transgene promoter.Current research in biotechnology · 2019Article
- Recurring genomic structural variation leads to clonal instability and loss of productivity.Biotechnology and bioengineering · 2019Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundRecombinant cell lines developed for therapeutic antibody production often suffer instability or lose recombinant protein expression during long-term culture. Heterogeneous gene expression among cell line subclones may result from epigenetic modifications of DNA or histones, the protein component of chromatin. We thus investigated in such cell lines, DNA methylation and the chromatin environment along the human eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) promoter in an antibody protein-expression vector which was integrated into the Chinese hamster ovary (CHO) cell line genome.
resultsWe analyzed four PT1-CHO cell lines which exhibited losses of protein expression at advanced passage number (>P35) growing in adherent conditions and in culture medium with 10 % FCS. These cell lines exhibited different integration sites and transgene copy numbers as determined by fluorescence in situ hybridization (FISH) and quantitative PCR (qPCR), respectively. By qRT-PCR, we analyzed the recombinant mRNA expression and correlated it with DNA methylation and with results from various approaches interrogating the chromatin landscape along the EEF1A1 promoter region. Each PT1-CHO cell line displayed specific epigenetic signatures or chromatin marks correlating with recombinant mRNA expression. The cell line with the lowest recombinant mRNA expression (PT1-1) was characterized by the highest nucleosome occupancy and displayed the lowest enrichment for histone marks associated with active transcription. In contrast, the cell line with the highest recombinant mRNA expression (PT1-55) exhibited the highest numbers of formaldehyde-assisted isolation of regulatory elements (FAIRE)-enriched regions, and was marked by enrichment for histone modifications H3K9ac and H3K9me3. Another cell line with the second highest recombinant mRNA transcription and the most stable protein expression (PT1-7) had the highest enrichments of the histone variants H3.3 and H2A.Z, and the histone modification H3K9ac. A further cell line (PT1-30) scored the highest enrichments for the bivalent marks H3K4me3 and H3K27me3. Finally, DNA methylation made a contribution, but only in the culture medium with reduced FCS or in a different expression vector.
conclusionsOur results suggest that the chromatin state along the EEF1A1 promoter region can help predict recombinant mRNA expression, and thus may assist in selecting desirable clones during cell line development for protein production.
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