title: Few regulatory metabolites coordinate expression of central metabolic genes in Escherichia coli.
abstract: Transcription networks consist of hundreds of transcription factors with thousands of often overlapping target genes. While we can reliably measure gene expression changes, we still understand relatively little why expression changes the way it does. How does a coordinated response emerge in such complex networks and how many input signals are necessary to achieve it? Here, we unravel the regulatory program of gene expression in Escherichia coli central carbon metabolism with more than 30 known transcription factors. Using a library of fluorescent transcriptional reporters, we comprehensively quantify the activity of central metabolic promoters in 26 environmental conditions. The expression patterns were dominated by growth rate-dependent global regulation for most central metabolic promoters in concert with highly condition-specific activation for only few promoters. Using an approximate mathematical description of promoter activity, we dissect the contribution of global and specific transcriptional regulation. About 70% of the total variance in promoter activity across conditions was explained by global transcriptional regulation. Correlating the remaining specific transcriptional regulation of each promoter with the cell's metabolome response across the same conditions identified potential regulatory metabolites. Remarkably, cyclic AMP, fructose-1,6-bisphosphate, and fructose-1-phosphate alone explained most of the specific transcriptional regulation through their interaction with the two major transcription factors Crp and Cra. Thus, a surprisingly simple regulatory program that relies on global transcriptional regulation and input from few intracellular metabolites appears to be sufficient to coordinate E. coli central metabolism and explain about 90% of the experimentally observed transcription changes in 100 genes.
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology, Zurich, Switzerland.
authors.forename: Karl
authors.identifier: 0000-0002-1884-7694
authors.initials: K
authors.lastname: Kochanowski
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology, Zurich, Switzerland.
authors.forename: Luca
authors.identifier: 0000-0001-6805-9410
authors.initials: L
authors.lastname: Gerosa
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Simon F
authors.identifier: 0000-0002-5935-6189
authors.initials: SF
authors.lastname: Brunner
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.|Life Science Zurich PhD Program on Systems Biology, Zurich, Switzerland.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Christodoulou
authors.affiliation: Institute of Molecular Biology & Biophysics, ETH Zurich, Zurich, Switzerland.
authors.forename: Yaroslav V
authors.identifier: 0000-0002-1479-7474
authors.initials: YV
authors.lastname: Nikolaev
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland sauer@imsb.biol.ethz.ch.
authors.forename: Uwe
authors.identifier: 0000-0002-5923-0770
authors.initials: U
authors.lastname: Sauer
mesh_terms: D004926:Escherichia coli / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005798:Genes, Bacterial; D017930:Genes, Reporter; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D008962:Models, Theoretical; D011401:Promoter Regions, Genetic
keywords: metabolism; modeling; network inference; transcription factors; transcriptional regulation