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 Sung; Wei Shou Hu; Miranda Gek Sim Yap; Muriel Bardor; Niranjan Nagarajan; Dong Yup Lee

doi:10.1016/j.cels.2017.04.009

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

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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 language	English (US)
Pages (from-to)	530-542.e6
Journal	Cell Systems
Volume	4
Issue number	5
DOIs	https://doi.org/10.1016/j.cels.2017.04.009
State	Published - May 24 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)

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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10.1016/j.cels.2017.04.009

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Yusufi, F. N. K., Lakshmanan, M., Ho, Y. S., Loo, B. L. W., Ariyaratne, P., Yang, Y., Ng, S. K., Tan, T. R. M., Yeo, H. C., Lim, H. L., Ng, S. W., Hiu, A. P., Chow, C. P., Wan, C., Chen, S., Teo, G., Song, G., Chin, J. X., Ruan, X., ... Lee, D. Y. (2017). Mammalian Systems Biotechnology Reveals Global Cellular Adaptations in a Recombinant CHO Cell Line. Cell Systems, 4(5), 530-542.e6. https://doi.org/10.1016/j.cels.2017.04.009

Yusufi, FNK, Lakshmanan, M, Ho, YS, Loo, BLW, Ariyaratne, P, Yang, Y, Ng, SK, Tan, TRM, Yeo, HC, Lim, HL, Ng, SW, Hiu, AP, Chow, CP, Wan, C, Chen, S, Teo, G, Song, G, Chin, JX, Ruan, X, Sung, KWK, Hu, WS, Yap, MGS, Bardor, M, Nagarajan, N & Lee, DY 2017, 'Mammalian Systems Biotechnology Reveals Global Cellular Adaptations in a Recombinant CHO Cell Line', Cell Systems, vol. 4, no. 5, pp. 530-542.e6. https://doi.org/10.1016/j.cels.2017.04.009

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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.",

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AU - Yusufi, Faraaz Noor Khan

AU - Lakshmanan, Meiyappan

AU - Ho, Ying Swan

AU - Loo, Bernard Liat Wen

AU - Ariyaratne, Pramila

AU - Yang, Yuansheng

AU - Ng, Say Kong

AU - Tan, Tessa Rui Min

AU - Yeo, Hock Chuan

AU - Lim, Hsueh Lee

AU - Ng, Sze Wai

AU - Hiu, Ai Ping

AU - Chow, Chung Ping

AU - Wan, Corrine

AU - Chen, Shuwen

AU - Teo, Gavin

AU - Song, Gao

AU - Chin, Ju Xin

AU - Ruan, Xiaoan

AU - Sung, Ken Wing Kin

AU - Hu, Wei Shou

AU - Yap, Miranda Gek Sim

AU - Bardor, Muriel

AU - Nagarajan, Niranjan

AU - Lee, Dong Yup

PY - 2017/5/24

Y1 - 2017/5/24

N2 - 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.

AB - 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.

KW - Chinese hamster ovary

KW - genome-scale metabolic model

KW - genomic rearrangements

KW - glycosylation

KW - lipid metabolism

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KW - tricistronic vector

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JF - Cell Systems

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ER -

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

Abstract

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