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The relationship between regulatory architecture and expression dynamics in transcriptional regulation of metabolic pathways

Abstract

A classic paradigm of gene regulation is the regulation of metabolic enzyme expression in response to changes in metabolite levels. In this study we generate a quantitative picture of the response of a number of amino acid biosynthesis pathways in S. cerevisiae in response to nutrient depletion. We find that a striking pattern emerges that couples the architecture of the transcriptional regulatory network to the gene expression response. In particular, we find that networks controlled by the intermediate-activated architecture (IAA), in which an intermediate metabolite of the pathway activates transcription of pathway genes, exhibit the following response: the enzyme immediately downstream of the regulatory metabolite is under the strongest transcriptional control, while the enzymes upstream of the regulatory intermediate are only weakly induced. This pattern of separation of responses is absent in pathways not controlled by the IAA network and can be explained by a fundamental observation regarding the 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 also be derived from a simple cost/benefit model of gene expression. Our results suggest that evolution of cis-regulation for metabolic pathway genes is strongly constrained by the overlying regulatory architecture.

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