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Burden-driven feedback control of gene expression

View ORCID ProfileF Ceroni, View ORCID ProfileS Furini, View ORCID ProfileTE Gorochowski, A Boo, View ORCID ProfileO Borkowski, YN Ladak, View ORCID ProfileAR Awan, View ORCID ProfileC Gilbert, View ORCID ProfileGB Stan, View ORCID ProfileT Ellis
doi: https://doi.org/10.1101/177030
F Ceroni
1Department of Chemical Engineering, Imperial College London,London, UK
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  • For correspondence: t.ellis@imperial.ac.uk g.stan@imperial.ac.uk
S Furini
2Department of Medical Biotechnologies, University of Siena,Siena, Italy
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TE Gorochowski
3BrisSynBio, University of Bristol, Life Sciences Building, Tyndall Avenue, Bristol, UK
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A Boo
4Centre for Synthetic Biology and Innovation, Imperial College London,London, UK
5Department of Bioengineering, Imperial College London,London, UK
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O Borkowski
4Centre for Synthetic Biology and Innovation, Imperial College London,London, UK
5Department of Bioengineering, Imperial College London,London, UK
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YN Ladak
6ITMAT Data Science Group, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
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AR Awan
4Centre for Synthetic Biology and Innovation, Imperial College London,London, UK
5Department of Bioengineering, Imperial College London,London, UK
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C Gilbert
4Centre for Synthetic Biology and Innovation, Imperial College London,London, UK
5Department of Bioengineering, Imperial College London,London, UK
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GB Stan
4Centre for Synthetic Biology and Innovation, Imperial College London,London, UK
5Department of Bioengineering, Imperial College London,London, UK
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  • For correspondence: t.ellis@imperial.ac.uk g.stan@imperial.ac.uk
T Ellis
4Centre for Synthetic Biology and Innovation, Imperial College London,London, UK
5Department of Bioengineering, Imperial College London,London, UK
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  • For correspondence: t.ellis@imperial.ac.uk g.stan@imperial.ac.uk
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ABSTRACT

Cells use feedback regulation to ensure robust growth despite fluctuating demands on resources and different environmental conditions. Yet the expression of foreign proteins from engineered constructs is an unnatural burden on resources that cells are not adapted for. Here we combined multiplex RNAseq with an in vivo assay to reveal the major transcriptional changes in two E. coli strains when a set of inducible synthetic constructs are expressed. We identified that native promoters related to the heat-shock response activate expression rapidly in response to synthetic expression, regardless of the construct. Using these promoters, we built a CRISPR/dCas9-based feedback regulation system that automatically adjusts synthetic construct expression in response to burden. Cells equipped with this general-use controller maintain capacity for native gene expression to ensure robust growth and as such outperform unregulated cells at protein yields in batch production. This engineered feedback is the first example of a universal, burden-based biomolecular control system and is modular, tuneable and portable.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted August 20, 2017.
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Burden-driven feedback control of gene expression
F Ceroni, S Furini, TE Gorochowski, A Boo, O Borkowski, YN Ladak, AR Awan, C Gilbert, GB Stan, T Ellis
bioRxiv 177030; doi: https://doi.org/10.1101/177030
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Burden-driven feedback control of gene expression
F Ceroni, S Furini, TE Gorochowski, A Boo, O Borkowski, YN Ladak, AR Awan, C Gilbert, GB Stan, T Ellis
bioRxiv 177030; doi: https://doi.org/10.1101/177030

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