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Regulatory architecture determines optimal regulation of gene expression in metabolic pathways.

ABSTRACT: In response to environmental changes, the connections ("arrows") in gene regulatory networks determine which genes modulate their expression, but the quantitative parameters of the network ("the numbers on the arrows") are equally important in determining the resulting phenotype. What are the objectives and constraints by which evolution determines these parameters? We explore these issues by analyzing gene expression changes in a number of yeast metabolic pathways in response to nutrient depletion. We find that a striking pattern emerges that couples the regulatory architecture of the pathway to the gene expression response. In particular, we find that pathways controlled by the intermediate metabolite activation (IMA) architecture, in which an intermediate metabolite activates transcription of pathway genes, exhibit the following response: the enzyme immediately downstream of the regulatory metabolite is under the strongest transcriptional control, whereas the induction of the enzymes upstream of the regulatory intermediate is relatively weak. This pattern of responses is absent in pathways not controlled by an IMA architecture. The observation can be explained by the constraint imposed by the fundamental feedback structure of the network, which places downstream enzymes under a negative feedback loop and upstream ones under a positive feedback loop. This general design principle for transcriptional control of a metabolic pathway can be derived from a simple cost/benefit model of gene expression, in which the observed pattern is an optimal solution. Our results suggest that the parameters regulating metabolic enzyme expression are optimized by evolution, under the strong constraint of the underlying regulatory architecture.

SUBMITTER: Chubukov V

PROVIDER: S-EPMC3324031 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Regulatory architecture determines optimal regulation of gene expression in metabolic pathways.

Chubukov Victor V Zuleta Ignacio A IA Li Hao H

Proceedings of the National Academy of Sciences of the United States of America 20120313 13

In response to environmental changes, the connections ("arrows") in gene regulatory networks determine which genes modulate their expression, but the quantitative parameters of the network ("the numbers on the arrows") are equally important in determining the resulting phenotype. What are the objectives and constraints by which evolution determines these parameters? We explore these issues by analyzing gene expression changes in a number of yeast metabolic pathways in response to nutrient deplet ...[more]

PMID: 22416120

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Project description:The dynamic features of a genetic network's response to environmental fluctuations represent essential functional specifications and thus may constrain the possible choices of network architecture and kinetic parameters. To explore the connection between dynamics and network design, we have analyzed a general regulatory architecture that is commonly found in many metabolic pathways. Such architecture is characterized by a dual control mechanism, with end product feedback inhibition and transcriptional regulation mediated by an intermediate metabolite. As a case study, we measured with high temporal resolution the induction profiles of the enzymes in the leucine biosynthetic pathway in response to leucine depletion, using an automated system for monitoring protein expression levels in single cells. All the genes in the pathway are known to be coregulated by the same transcription factors, but we observed drastically different dynamic responses for enzymes upstream and immediately downstream of the key control point-the intermediate metabolite alpha-isopropylmalate (alphaIPM), which couples metabolic activity to transcriptional regulation. Analysis based on genetic perturbations suggests that the observed dynamics are due to differential regulation by the leucine branch-specific transcription factor Leu3, and that the downstream enzymes are strictly controlled and highly expressed only when alphaIPM is available. These observations allow us to build a simplified mathematical model that accounts for the observed dynamics and can correctly predict the pathway's response to new perturbations. Our model also suggests that transient dynamics and steady state can be separately tuned and that the high induction levels of the downstream enzymes are necessary for fast leucine recovery. It is likely that principles emerging from this work can reveal how gene regulation has evolved to optimize performance in other metabolic pathways with similar architecture.

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Regulatory architecture determines optimal regulation of gene expression in metabolic pathways.

Publications

Regulatory architecture determines optimal regulation of gene expression in metabolic pathways.

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