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Dissecting specific and global transcriptional regulation of bacterial gene expression

Luca Gerosa, Karl Kochanowski, Matthias Heinemann, Uwe Sauer

Author Affiliations

  1. Luca Gerosa1,2,,
  2. Karl Kochanowski1,3,,
  3. Matthias Heinemann1,4 and
  4. Uwe Sauer*,1,3
  1. 1 Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
  2. 2 Life Science Zurich PhD Program on Systems Biology of Complex Diseases, Zurich, Switzerland
  3. 3 Life Science Zurich PhD Program on Systems Biology, Zurich, Switzerland
  4. 4 Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
  1. *Corresponding author. Institute of Molecular Systems Biology, ETH Zurich, Wolfgang Pauli Strasse 16, Zurich 8093, Switzerland. Tel.:+41 44633 3672; Fax:+41 44633 1051; E‐mail: sauer{at}imsb.biol.ethz.ch
  1. These authors contributed equally to this work.

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Abstract

Gene expression is regulated by specific transcriptional circuits but also by the global expression machinery as a function of growth. Simultaneous specific and global regulation thus constitutes an additional—but often neglected—layer of complexity in gene expression. Here, we develop an experimental‐computational approach to dissect specific and global regulation in the bacterium Escherichia coli. By using fluorescent promoter reporters, we show that global regulation is growth rate dependent not only during steady state but also during dynamic changes in growth rate and can be quantified through two promoter‐specific parameters. By applying our approach to arginine biosynthesis, we obtain a quantitative understanding of both specific and global regulation that allows accurate prediction of the temporal response to simultaneous perturbations in arginine availability and growth rate. We thereby uncover two principles of joint regulation: (i) specific regulation by repression dominates the transcriptional response during metabolic steady states, largely repressing the biosynthesis genes even when biosynthesis is required and (ii) global regulation sets the maximum promoter activity that is exploited during the transition between steady states.

Synopsis

An experimental‐computational approach is applied to dissect the contribution of specific transcription factor‐mediated versus global growth‐dependent regulation to bacterial gene expression, and obtain a quantitative understanding of dynamic adaptations in arginine biosynthesis of E. coli.

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  • We present a model‐based approach to quantitatively dissect simultaneous contributions from specific transcription factors and the global growth status to bacterial gene expression, based on parameter inference from GFP‐based promoter activity measurements.

  • We show that growth rate can be used to predict the unregulated expression baseline of a gene, since growth rate dependence of global regulation occurs both in steady state and during transient changes in growth rate.

  • We obtain a quantitative understanding of both specific and global regulation in arginine biosynthesis, as demonstrated by accurate model‐based predictions of complex transient gene‐expression responses to simultaneous perturbation in growth rate and arginine availability.

  • We uncover two principles of joint regulation of the arginine biosynthesis pathway: (i) specific regulation by repression dominates in steady metabolic states and (ii) global regulation sets the maximal expression reachable during transition between steady metabolic states.

Mol Syst Biol. 9: 658

  • Received December 18, 2012.
  • Accepted March 6, 2013.

This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

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