Microevolutionary dynamics of eccDNA in Chinese hamster ovary cells grown in fed-batch cultures under control and lactate-stressed conditions
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Abstract
Chinese hamster ovary (CHO) cell lines are widely used to manufacture biopharmaceuticals. However, CHO cells are not an optimal expression host due to the intrinsic plasticity of the CHO genome. Genome plasticity can lead to chromosomal rearrangements, transgene exclusion, and phenotypic drift. A poorly understood genomic element of CHO cell line instability is extrachromosomal circular DNA (eccDNA) in gene expression and regulation. EccDNA can facilitate ultra-high gene expression and are found within many eukaryotes including humans, yeast, and plants. EccDNA confers genetic heterogeneity, providing selective advantages to individual cells in response to dynamic environments. In CHO cell cultures, maintaining genetic homogeneity is critical to ensuring consistent productivity and product quality. Understanding eccDNA structure, function, and microevolutionary dynamics under various culture conditions could reveal potential engineering targets for cell line optimization. In this study, eccDNA sequences were investigated at the beginning and end of two-week fed-batch cultures in an ambr ® 250 bioreactor under control and lactate-stressed conditions. This work characterized structure and function of eccDNA in a CHO-K1 clone. Gene annotation identified 1551 unique eccDNA genes including cancer driver genes and genes involved in protein production. Furthermore, RNA-seq data is integrated to identify transcriptionally active eccDNA genes.
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Exponential accumulation of lactate near the end of the lactate-stressed cultures could be attributed to extrachromosomal overexpression of Akr1b1, a gene closely linked to Warburg metabolism in some cancer types.
“Exponential accumulation of lactate near the end of the lactate‐stressed cultures could be attributed to extrachromosomal overexpression of Akr1b1, a gene closely linked to Warburg metabolism in some cancer types. 44”
From Dynamic <scp>pH</scp> profiles drive higher cell‐specific and volumetric productivity (2026) · cites this paper as [44]
The Discussion (page unavailable) reports that Akr1b1 was found on eccDNA and upregulated in lactate-stressed Day 12 cultures; it suggests that its overexpression could have contributed to lactate accumulation starting on Day 8 and links it to Warburg effects in cancer. It does not describe the accumulation as exponential, and the Discussion says the transcripts’ chromosomal versus eccDNA origin cannot be determined with certainty. (LLM, conf=0.86)
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Self-citationQi, K., Liu, Z., Amevor, F. K., Xu, D., Zhu, W., Li, T., Wang, Y., Wu, L., Shu, G., & Zhao, X. (2025) · Biotechnology Advances · doi:10.1016/j.biotechadv.2025.108693 · Cited by 3 · see citing works
Beyond chromosomes: exploring the diverse functions of extrachromosomal circular DNA
Chen, Y., Wang, J., Liu, X., Li, X., Li, Z., & Li, H. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.10.005 · Cited by 3 · see citing works
Multi‐Scale Hybrid Modeling to Predict Cell Culture Process With Metabolic Phase Transitions
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Dynamic <scp>pH</scp> profiles drive higher cell‐specific and volumetric productivity
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Application of Deep Learning in the Identification of Extrachromosomal Circular DNA (eccDNA)
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Comparing kinetic versus stoichiometric priorities in hybrid models of CHO metabolism
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How Does Genetic Drift Impact the Safety of Cell-Cultivated Products?
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- Authors
- Chitwood, D. G., Wang, Q., Klaubert, S. R., Green, K., Wu, C. H., Harcum, S. W., & Saski, C. A.
- Affiliations
- Clemson University (US)
- University of Delaware (US)
- University of South Carolina (US)
- Corresponding author
- Saski, Christopher A.
- Venue
- Scientific Reports
- Published
- 2023-01-21
- Volume
- 13
- Issue
- 1
- Pages
- 1200-1200
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC9862248
- OpenAlex
- W4317655954
- Cited by
- 12
- References
- 98
- Citations by year
- 2026: 3 · 2025: 7 · 2023: 2
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (IIP- 1624641)
- Advanced Mammalian Biomanufacturing Innovation Center
- 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 › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- extrachromosomal circular DNA, CHO cells, CHO-K1 cells, fed-batch fermentation, microevolution, genome plasticity, biopharmaceutical manufacturing, bioreactors
- MeSH terms
- Animals, Cricetulus, DNA, Cricetinae, Humans, CHO Cells, Genome, Lactic Acid, Batch Cell Culture Techniques
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