Mammalian Systems Biotechnology Reveals Global Cellular Adaptations in a Recombinant CHO Cell Line

Faraaz Noor Khan Yusufi, Meiyappan Lakshmanan, Ying Swan Ho, Bernard Liat Wen Loo, Pramila Ariyaratne, Yuansheng Yang, Say Kong Ng, Tessa Rui Min Tan, Hock Chuan Yeo, Hsueh Lee Lim, Sze Wai Ng, Ai Ping Hiu, Chung Ping Chow, Corrine Wan, Shuwen Chen, Gavin Teo, Gao Song, Ju Xin Chin, Xiaoan Ruan, Ken Wing Kin SungWei Shou Hu, Miranda Gek Sim Yap, Muriel Bardor, Niranjan Nagarajan, Dong Yup Lee

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Effective development of host cells for therapeutic protein production is hampered by the poor characterization of cellular transfection. Here, we employed a multi-omics-based systems biotechnology approach to elucidate the genotypic and phenotypic differences between a wild-type and recombinant antibody-producing Chinese hamster ovary (CHO) cell line. At the genomic level, we observed extensive rearrangements in specific targeted loci linked to transgene integration sites. Transcriptional re-wiring of DNA damage repair and cellular metabolism in the antibody producer, via changes in gene copy numbers, was also detected. Subsequent integration of transcriptomic data with a genome-scale metabolic model showed a substantial increase in energy metabolism in the antibody producer. Metabolomics, lipidomics, and glycomics analyses revealed an elevation in long-chain lipid species, potentially associated with protein transport and secretion requirements, and a surprising stability of N-glycosylation profiles between both cell lines. Overall, the proposed knowledge-based systems biotechnology framework can further accelerate mammalian cell-line engineering in a targeted manner.

Original languageEnglish (US)
Pages (from-to)530-542.e6
JournalCell Systems
Volume4
Issue number5
DOIs
StatePublished - May 24 2017

Keywords

  • Chinese hamster ovary
  • genome-scale metabolic model
  • genomic rearrangements
  • glycosylation
  • lipid metabolism
  • monoclonal antibody-producing cell line
  • systems biotechnology
  • tricistronic vector

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