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Programming mRNA decay to modulate synthetic circuit resource allocation

View ORCID ProfileOphelia S. Venturelli, Mika Tei, Stefan Bauer, Leanne Jade G. Chan, Christopher J. Petzold, View ORCID ProfileAdam P. Arkin
doi: https://doi.org/10.1101/079939
Ophelia S. Venturelli
1California Institute for Quantitative Biosciences, University of California Berkeley, Berkeley CA
2Department of Bioengineering, University of California Berkeley, Berkeley CA
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  • For correspondence: aparkin@lbl.gov venturelli@wisc.edu
Mika Tei
1California Institute for Quantitative Biosciences, University of California Berkeley, Berkeley CA
2Department of Bioengineering, University of California Berkeley, Berkeley CA
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Stefan Bauer
3Energy Biosciences Institute, University of California Berkeley, Berkeley CA
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Leanne Jade G. Chan
4Joint BioEnergy Institute and Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley CA
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Christopher J. Petzold
4Joint BioEnergy Institute and Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley CA
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Adam P. Arkin
1California Institute for Quantitative Biosciences, University of California Berkeley, Berkeley CA
2Department of Bioengineering, University of California Berkeley, Berkeley CA
3Energy Biosciences Institute, University of California Berkeley, Berkeley CA
5Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley CA
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  • For correspondence: aparkin@lbl.gov venturelli@wisc.edu
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ABSTRACT

Synthetic biomolecular networks embedded in host-cells compete with cellular processes for limited intracellular resources. Resource utilization is a major variable that impacts synthetic circuit behavior. Here we show that intracellular resources could be diverted from cellular operations to a synthetic circuit by programming global mRNA decay using the sequence-dependent endoribonuclease MazF. Synthetic circuit genes were protected from MazF activity by recoding the gene sequence to eliminate recognition sites, while preserving the amino acid sequence. The expression of a protected fluorescent reporter and the metabolic flux of a high-value metabolite gluconate were significantly enhanced using this genome-scale control strategy. Proteomics measurements discovered a key host translation factor in need of protection to optimize the resource redistribution activity. A dynamic computational model demonstrated that the MazF mRNA-decay feedback loop achieved proportional control of MazF levels in an optimal operating regime. RNA-seq time-series measurements of MazF-induced cells elucidated the dynamic shifts in the transcript abundance and discovered regulatory design elements that could be used to expand the control mechanisms of the MazF resource allocator. Together, these results demonstrated that manipulation of resource allocation is a tunable parameter that can be used to redirect resources away from cellular processes to synthetic circuits to enhance target functions.

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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-NC-ND 4.0 International license.
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Posted October 09, 2016.
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Programming mRNA decay to modulate synthetic circuit resource allocation
Ophelia S. Venturelli, Mika Tei, Stefan Bauer, Leanne Jade G. Chan, Christopher J. Petzold, Adam P. Arkin
bioRxiv 079939; doi: https://doi.org/10.1101/079939
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Programming mRNA decay to modulate synthetic circuit resource allocation
Ophelia S. Venturelli, Mika Tei, Stefan Bauer, Leanne Jade G. Chan, Christopher J. Petzold, Adam P. Arkin
bioRxiv 079939; doi: https://doi.org/10.1101/079939

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