Abstract
ABSTRACTGlobal transcriptional regulators coordinate complex genetic interactions that bestow better adaptability for an organism against external and internal perturbations. These transcriptional regulators are known to control an enormous array of genes with diverse functionalities. However, regulator-driven molecular mechanisms that underpin precisely tuned translational and metabolic processes conducive for rapid exponential growth remain obscure. Here, we comprehensively reveal the fundamental role of global transcriptional regulators FNR, ArcA, and IHF in sustaining translational and metabolic efficiency under glucose fermentative conditions in Escherichia coli. By integrating high-throughput gene expression profiles and absolute intracellular metabolite concentrations, we illustrate that these regulators are crucial in maintaining nitrogen homeostasis, govern expression of otherwise unnecessary or hedging genes, and exert tight control on metabolic bottleneck steps. Furthermore, we characterize changes in expression and activity profiles of other coregulators associated with these dysregulated metabolic pathways, determining the regulatory interactions within the transcriptional regulatory network. Such systematic findings emphasize their importance in optimizing the proteome allocation toward metabolic enzymes as well as ribosomes, facilitating condition-specific phenotypic outcomes. Consequentially, we reveal that disruption of this inherent trade-off between ribosome and metabolic proteome economy due to the loss of regulators resulted in lowered growth rates. Moreover, our findings reinforce that the accumulations of intracellular metabolites in the event of proteome repartitions negatively affects the glucose uptake. Overall, by extending the three-partition proteome allocation theory concordant with multi-omics measurements, we elucidate the physiological consequences of loss of global regulators on central carbon metabolism restraining the organism to attain maximal biomass synthesis.IMPORTANCE Cellular proteome allocation in response to environmental or internal perturbations governs their eventual phenotypic outcome. This entails striking an effective balance between amino acid biosynthesis by metabolic proteins and its consumption by ribosomes. However, the global transcriptional regulator-driven molecular mechanisms that underpin their coordination remains unexplored. Here, we emphasize that global transcriptional regulators, known to control expression of a myriad of genes, are fundamental for precisely tuning the translational and metabolic efficiencies that define the growth optimality. Towards this, we systematically characterized the single deletion effect of FNR, ArcA, and IHF regulators of Escherichia coli on exponential growth under anaerobic glucose fermentative conditions. Their absence disrupts the stringency of proteome allocation, which manifests as impairment in key metabolic processes and an accumulation of intracellular metabolites. Furthermore, by incorporating an extension to the empirical growth laws, we quantitatively demonstrate the general design principles underlying the existence of these regulators in E. coli.
Highlights
Global transcriptional regulators coordinate complex genetic interactions that bestow better adaptability for an organism against external and internal perturbations
Under nutrient-rich conditions, proteome allocation toward ribosomes is augmented to enable faster growth with reduced synthesis of the metabolic proteome. This proteome allocation theory can be explained by the trade-off existing between metabolic flux involved in generating the precursors and amino acids by the metabolic proteome and protein synthesis flux utilizing the amino acids by ribosomes, which results in balanced exponential growth [4]
To address the transcriptomic changes caused by the disruption of global regulators, namely, FNR, ArcA, and IHF, in E. coli K-12 MG1655 under anaerobic fermentation in glucose minimal medium, we performed a high-coverage RNA sequencing (RNA-seq) experiment around the mid-exponential phase of growth
Summary
Global transcriptional regulators coordinate complex genetic interactions that bestow better adaptability for an organism against external and internal perturbations. We systematically characterized the single deletion effect of FNR, ArcA, and IHF regulators of Escherichia coli on exponential growth under anaerobic glucose fermentative conditions Their absence disrupts the stringency of proteome allocation, which manifests as impairment in key metabolic processes and an accumulation of intracellular metabolites. This proteome allocation theory can be explained by the trade-off existing between metabolic flux involved in generating the precursors and amino acids by the metabolic proteome and protein synthesis flux utilizing the amino acids by ribosomes, which results in balanced exponential growth [4] Such metabolic and translational efficiencies facilitated by the endogenous proteome of the central carbon metabolism and ribosomes entail bacterial growth to be precisely controlled by the joint effects of global physiological machinery (e.g., RNA polymerase, ribosomes, and alarmones) and transcriptional regulators [4,5,6,7,8]. Emphasis on changes in gene expression or activity profiles on their coregulators or local regulators modulating specific pathways highlights their widespread interactions within the transcriptional regulatory network
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