Promoter selection reduces phenotypic heterogeneity and improves bioproduction
File(s)
Published version (in press)
Author(s)
Type
Journal Article
Abstract
Cell-to-cell heterogeneity leads to the formation of subpopulations within an isogenic population, resulting in the coexistence of high and low producer cells. However, the impact of this phenotypic heterogeneity on bioproduction has been overlooked. Using flow cytometry to analyse commonly used yeast promoters, we found that many display macro-heterogeneity, generating multiple discrete subpopulations. Additionally, by regressing single-cell protein expression on single-cell RNA sequencing data, we explored the use of predictive models as a guide for selecting promoters with more homogeneous expression at desired expression levels. As a proof of concept, we engineered an improved lycopene pathway by substituting homogeneous promoters for macro-heterogeneous ones and implemented single-cell Raman spectroscopy to demonstrate up to a threefold increase in single-cell and bulk lycopene production. Overall, our results show that promoter heterogeneity can have a large impact on microbial bioprocesses and that the selection of homogeneous promoters can achieve more efficient production in a metabolically engineered pathway.
Date Issued
2026-08-27
Date Acceptance
2026-08-04
Citation
Trends in Biotechnology, 2026
ISSN
0167-7799
Publisher
Cell Press
Start Page
S0167-7799(26)00337-9
Journal / Book Title
Trends in Biotechnology
Copyright Statement
© 2026 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42648918
PII: S0167-7799(26)00337-9
Subjects
metabolic engineering
microbial production
phenotypic heterogeneity
promoter homogenisation
single-cell Raman spectroscopy
subpopulations
Publication Status
Published online
Coverage Spatial
England
Date Publish Online
2026-08-27