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Deciphering the transcriptional regulatory logic of amino acid metabolism

Nature Chemical Biology volume 8, pages 65–71 (2012)Cite this article

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Abstract

Although metabolic networks have been reconstructed on a genome scale, the corresponding reconstruction and integration of governing transcriptional regulatory networks has not been fully achieved. Here we reconstruct such an integrated network for amino acid metabolism in Escherichia coli. Analysis of ChIP-chip and gene expression data for the transcription factors ArgR, Lrp and TrpR showed that 19 out of 20 amino acid biosynthetic pathways are either directly or indirectly controlled by these regulators. Classifying the regulated genes into three functional categories of transport, biosynthesis and metabolism leads to the elucidation of regulatory motifs that constitute the integrated network's basic building blocks. The regulatory logic of these motifs was determined on the basis of relationships between transcription factor binding and changes in the amount of transcript in response to exogenous amino acids. Remarkably, the resulting logic shows how amino acids are differentiated as signaling and nutrient molecules, revealing the overarching regulatory principles of the amino acid stimulon.

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Figure 1: Genome-wide distribution of ArgR- and TrpR-binding regions (regulatory code analysis).
Figure 2: Functional classification of genes directly regulated by ArgR, Lrp and TrpR.
Figure 3: Delineation of amino acid biosynthetic pathways and transport systems in E. coli (topological analysis).
Figure 4: Causal relationships between direct associations of transcription factors and the changes in RNA transcript levels of genes (functional analysis).
Figure 5: Reconstruction of regulatory motif and the logical structures of connected-circuit motifs in response to the exogenous amino acids (network analysis).

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Acknowledgements

The authors thank M. Abrams and J. Lerman for critical reading of the manuscript. The US National Institutes of Health (through grant GM062791) and the Office of Science–Biological and Environmental Research, US Department of Energy (through grant DE-FOA-0000143) supported this work.

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  1. Byung-Kwan Cho & Young-Seoub Park

    Present address: Current addresses: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejoen, Korea (B.-K.C.) and Mogam Biotechnology Research Institute, Yongin, Korea (Y.-S.P.).,

Authors and Affiliations

  1. Department of Bioengineering, University of California at San Diego, La Jolla, California, USA

    Byung-Kwan Cho, Stephen Federowicz, Young-Seoub Park, Karsten Zengler & Bernhard Ø Palsson

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Contributions

B.-K.C. and B.Ø.P. conceived the study. B.-K.C. and Y.-S.P. designed and performed ChIP-chip and gene expression experiments. B.-K.C. and S.F. analyzed data with contributions from K.Z. The manuscript was written by B.-K.C., S.F., K.Z. and B.Ø.P.

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Correspondence to Byung-Kwan Cho or Bernhard Ø Palsson.

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Cho, BK., Federowicz, S., Park, YS. et al. Deciphering the transcriptional regulatory logic of amino acid metabolism. Nat Chem Biol 8, 65–71 (2012). https://doi.org/10.1038/nchembio.710

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