Programming mRNA decay to modulate synthetic circuit resource allocation

Ophelia S. Venturelli (), Mika Tei, Stefan Bauer, Leanne Jade G. Chan, Christopher J. Petzold and Adam P Arkin ()
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Ophelia S. Venturelli: California Institute for Quantitative Biosciences, University of California Berkeley
Mika Tei: California Institute for Quantitative Biosciences, University of California Berkeley
Stefan Bauer: Energy Biosciences Institute, University of California Berkeley
Leanne Jade G. Chan: Lawrence Berkeley National Laboratory
Christopher J. Petzold: Lawrence Berkeley National Laboratory
Adam P Arkin: California Institute for Quantitative Biosciences, University of California Berkeley

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Synthetic circuits embedded in host cells compete with cellular processes for limited intracellular resources. Here we show how funnelling of cellular resources, after global transcriptome degradation by the sequence-dependent endoribonuclease MazF, to a synthetic circuit can increase production. Target genes are 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 flux of a high-value metabolite are significantly enhanced using this genome-scale control strategy. Proteomics measurements discover a host factor in need of protection to improve resource redistribution activity. A computational model demonstrates that the MazF mRNA-decay feedback loop enables proportional control of MazF in an optimal operating regime. Transcriptional profiling of MazF-induced cells elucidates the dynamic shifts in transcript abundance and discovers regulatory design elements. Altogether, our results suggest that manipulation of cellular resource allocation is a key control parameter for synthetic circuit design.

Date: 2017
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DOI: 10.1038/ncomms15128

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