Harnessing the central dogma for stringent multi-level control of gene expression

• Published in: Nature communications Vol. 12; no. 1; pp. 1738 - 11
• Main Authors: Greco, F. Veronica, Pandi, Amir, Erb, Tobias J., Grierson, Claire S., Gorochowski, Thomas E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14/35; 49/31; 631/553/2691; 631/553/552; Biochemical Phenomena; Biocompatibility; Cell viability; Escherichia coli - genetics; Gene expression; Gene Expression Regulation; Gene regulation; Genetic Techniques; Humanities and Social Sciences; Humans; multidisciplinary; Noise; Protein Biosynthesis; Proteins; Science; Science (multidisciplinary); Signal Transduction; Switches; Synthetic Biology; Transcription; Transcription, Genetic; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21995-7

Strictly controlled inducible gene expression is crucial when engineering biological systems where even tiny amounts of a protein have a large impact on function or host cell viability. In these cases, leaky protein production must be avoided, but without affecting the achievable range of expression. Here, we demonstrate how the central dogma offers a simple solution to this challenge. By simultaneously regulating transcription and translation, we show how basal expression of an inducible system can be reduced, with little impact on the maximum expression rate. Using this approach, we create several stringent expression systems displaying >1000-fold change in their output after induction and show how multi-level regulation can suppress transcriptional noise and create digital-like switches between ‘on’ and ‘off’ states. These tools will aid those working with toxic genes or requiring precise regulation and propagation of cellular signals, plus illustrate the value of more diverse regulatory designs for synthetic biology. Inducible gene expression systems should minimise leaky output and offer a large achievable range of expression. Here, the authors regulate transcription and translation together to suppress noise and create digital-like responses, while maintaining a large expression range in vivo and in vitro.