Shared control of gene expression in bacteria by transcription factors and global physiology of the cell

• Published in: Molecular systems biology 2013, Vol.9 (1), p.634-n/a
• Main Authors: Berthoumieux, Sara, de Jong, Hidde, Baptist, Guillaume, Pinel, Corinne, Ranquet, Caroline, Ropers, Delphine, Geiselmann, Johannes
• Format: Article
• Language: English
• Subjects: Automatic Control Engineering; bacterial physiology; Bacteriology; Binding sites; Biochemistry, Molecular Biology; Bioinformatics; Biotechnology; Carbon; Carbon - metabolism; Circuits; Computer Science; Confidence intervals; Cyclic AMP; Cyclic AMP - genetics; Cyclic AMP - metabolism; Cyclic AMP Receptor Protein - genetics; Cyclic AMP Receptor Protein - metabolism; Data analysis; Deoxyribonucleic acid; DNA; Dynamical Systems; E coli; EMBO23; EMBO26; Engineering Sciences; Escherichia coli; Escherichia coli - growth & development; Escherichia coli - physiology; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Factor For Inversion Stimulation Protein - genetics; Factor For Inversion Stimulation Protein - metabolism; Gene expression; Gene Expression Regulation, Bacterial; Gene Regulatory Networks; Genomics; Glucose; Growth rate; Life Sciences; Mathematics; Metabolism; Metabolites; Microbiology and Parasitology; Models, Biological; Molecular biology; Molecular Networks; Optimization and Control; Phase transitions; Physiological effects; Physiology; Plasmids; Proteins; Quantitative Methods; Regulators; Reproducibility of Results; RNA polymerase; Signal and Image Processing; systems biology; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/msb.2012.70

Gene expression is controlled by the joint effect of (i) the global physiological state of the cell, in particular the activity of the gene expression machinery, and (ii) DNA‐binding transcription factors and other specific regulators. We present a model‐based approach to distinguish between these two effects using time‐resolved measurements of promoter activities. We demonstrate the strength of the approach by analyzing a circuit involved in the regulation of carbon metabolism in E. coli . Our results show that the transcriptional response of the network is controlled by the physiological state of the cell and the signaling metabolite cyclic AMP (cAMP). The absence of a strong regulatory effect of transcription factors suggests that they are not the main coordinators of gene expression changes during growth transitions, but rather that they complement the effect of global physiological control mechanisms. This change of perspective has important consequences for the interpretation of transcriptome data and the design of biological networks in biotechnology and synthetic biology. A simple, parameterless mathematical model, in combination with real‐time monitoring of promoter activities, shows how control of gene expression in bacteria is shared between transcription factors and global physiological effects. Synopsis A simple, parameterless mathematical model, in combination with real‐time monitoring of promoter activities, shows how control of gene expression in bacteria is shared between transcription factors and global physiological effects. We present an approach based on a simple, paramaterless mathematical model to analyze the control of gene expression by transcription factors and the global physiological state of the cell. We illustrate the strength of this approach by means of time‐resolved measurements of the transcriptional activities of genes in a central regulatory circuit in Escherichia coli . We conclude that global physiological effects rather than transcription factors dominate the control of gene expression during a growth transition. Our results call for a reappraisal of the role of transcription factors, which may be most appropriately viewed as complementing and finetuning global control exerted by the physiological state of the cell.