An in vivo gene amplification system for high level expression in Saccharomyces cerevisiae

Bingyin Peng (), Lygie Esquirol, Zeyu Lu, Qianyi Shen, Li Chen Cheah, Christopher B. Howard, Colin Scott, Matt Trau, Geoff Dumsday and Claudia E. Vickers ()
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Bingyin Peng: The University of Queensland
Lygie Esquirol: The University of Queensland
Zeyu Lu: The University of Queensland
Qianyi Shen: The University of Queensland
Li Chen Cheah: The University of Queensland
Christopher B. Howard: The University of Queensland
Colin Scott: Commonwealth Scientific and Industrial Research Organisation (CSIRO)
Matt Trau: The University of Queensland
Geoff Dumsday: CSIRO Manufacturing
Claudia E. Vickers: Commonwealth Scientific and Industrial Research Organisation (CSIRO)

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Bottlenecks in metabolic pathways due to insufficient gene expression levels remain a significant problem for industrial bioproduction using microbial cell factories. Increasing gene dosage can overcome these bottlenecks, but current approaches suffer from numerous drawbacks. Here, we describe HapAmp, a method that uses haploinsufficiency as evolutionary force to drive in vivo gene amplification. HapAmp enables efficient, titratable, and stable integration of heterologous gene copies, delivering up to 47 copies onto the yeast genome. The method is exemplified in metabolic engineering to significantly improve production of the sesquiterpene nerolidol, the monoterpene limonene, and the tetraterpene lycopene. Limonene titre is improved by 20-fold in a single engineering step, delivering ∼1 g L−1 in the flask cultivation. We also show a significant increase in heterologous protein production in yeast. HapAmp is an efficient approach to unlock metabolic bottlenecks rapidly for development of microbial cell factories.

Date: 2022
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DOI: 10.1038/s41467-022-30529-8

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