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Activity motifs reveal principles of timing in transcriptional control of the yeast metabolic network

Nature Biotechnology volume 26, pages 1251–1259 (2008)Cite this article

Abstract

Significant insight about biological networks arises from the study of network motifs—overly abundant network subgraphs1,2—but such wiring patterns do not specify when and how potential routes within a cellular network are used. To address this limitation, we introduce activity motifs, which capture patterns in the dynamic use of a network. Using this framework to analyze transcription in Saccharomyces cerevisiae metabolism, we find that cells use different timing activity motifs to optimize transcription timing in response to changing conditions: forward activation to produce metabolic compounds efficiently, backward shutoff to rapidly stop production of a detrimental product and synchronized activation for co-production of metabolites required for the same reaction. Measuring protein abundance over a time course reveals that mRNA timing motifs also occur at the protein level. Timing motifs significantly overlap with binding activity motifs, where genes in a linear chain have ordered binding affinity to a transcription factor, suggesting a mechanism for ordered transcription. Finely timed transcriptional regulation is therefore abundant in yeast metabolism, optimizing the organism's adaptation to new environmental conditions.

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Figure 1: Activity motifs overlay functional data over known network wiring structure.
Figure 2: Timing activity motifs across conditions.
Figure 3: Multiple activity motifs overlay the pentose phosphate pathway and glycerol biosynthesis.
Figure 4: Functional characterization of activity motifs.
Figure 5: Protein timing motifs in response to DTT.

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Acknowledgements

Work was supported by the National Science Foundation under grant BDI-0345474. A.R. was supported by a Career award at the Scientific Interface from the Burroughs Wellcome Fund and by NIGMS. J.W. was supported by the Howard Hughes Medical Institute. The authors thank Trey Ideker, Dwight Kuo, Craig Mak and Eran Segal for assistance in early stages of this project, and Dana Pe'er and especially Eric Lander for useful discussions.

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  1. Gal Chechik

    Present address: Present address: Google Research, 1600 Amphitheater Parkway, Mountain View, California 94043, USA.,

Authors and Affiliations

  1. Department of Computer Science, Stanford University, Stanford, 94305, California, USA

    Gal Chechik & Daphne Koller

  2. Howard Hughes Medical Foundation and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, 94143, California, USA

    Eugene Oh & Jonathan Weissman

  3. Departments of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA

    Oliver Rando

  4. Department of Biology, Massachusetts Institute of Technology and the Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Aviv Regev

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Contributions

G.C. and D.K. conceived of the study and developed the method. A.R. participated in the method development and designed and executed the biological analysis. O.R. designed and executed the microarray experiments. The protein abundance experiments were designed by E.O., J.W., G.C. and D.K., executed by E.O. and analyzed by G.C. and D.K. G.C., D.K. and A.R. wrote the manuscript and developed the figures.

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Correspondence to Aviv Regev or Daphne Koller.

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Chechik, G., Oh, E., Rando, O. et al. Activity motifs reveal principles of timing in transcriptional control of the yeast metabolic network. Nat Biotechnol 26, 1251–1259 (2008). https://doi.org/10.1038/nbt.1499

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