Abstract
Models of gene expression considering host–circuit interactions are relevant for understanding both the strategies and associated trade-offs that cell endogenous genes have evolved and for the efficient design of heterologous protein expression systems and synthetic genetic circuits. Here, we consider a small-size model of gene expression dynamics in bacterial cells accounting for host–circuit interactions due to limited cellular resources. We define the cellular resources recruitment strength as a key functional coefficient that explains the distribution of resources among the host and the genes of interest and the relationship between the usage of resources and cell growth. This functional coefficient explicitly takes into account lab-accessible gene expression characteristics, such as promoter and ribosome binding site (RBS) strengths, capturing their interplay with the growth-dependent flux of available free cell resources. Despite its simplicity, the model captures the differential role of promoter and RBS strengths in the distribution of protein mass fractions as a function of growth rate and the optimal protein synthesis rate with remarkable fit to the experimental data from the literature for Escherichia coli. This allows us to explain why endogenous genes have evolved different strategies in the expression space and also makes the model suitable for model-based design of exogenous synthetic gene expression systems with desired characteristics.
Highlights
The interrelations among the cell environment from which the cell uptakes substrates, its metabolism, and the engagement of cell resources needed for gene expression result in host−circuit interactions between gene circuits and their cell host
These do contribute to cell mass, but not to cell growth, akin to the consideration of unproductive proteins used in ref 9
We focused on varying the expression space i.e., the gene induction space defined by the values of the mature mRNA synthesis rate and the effective ribosome binding site (RBS) strength at the same values of cell growth conditions and intracellular substrate availability
Summary
The interrelations among the cell environment from which the cell uptakes substrates, its metabolism, and the engagement of cell resources needed for gene expression result in host−circuit interactions between gene circuits and their cell host. The overexpression of exogenous genes by a genetically modified microorganism as well as the production of metabolites by the addition and/or modification of their metabolic pathways introduce a metabolic load that takes the microorganism off its natural state.[3] The resulting competition for common shared cell resources affects cell growth and introduces spurious dynamics,[4] leading to problems of malfunctioning of the synthetic circuit. It triggers its elimination by evolutionary mechanisms trying to restore the natural optimal state.[5]
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