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Metabolic gene regulation in a dynamically changing environment.

ABSTRACT: Natural selection dictates that cells constantly adapt to dynamically changing environments in a context-dependent manner. Gene-regulatory networks often mediate the cellular response to perturbation, and an understanding of cellular adaptation will require experimental approaches aimed at subjecting cells to a dynamic environment that mimics their natural habitat. Here we monitor the response of Saccharomyces cerevisiae metabolic gene regulation to periodic changes in the external carbon source by using a microfluidic platform that allows precise, dynamic control over environmental conditions. We show that the metabolic system acts as a low-pass filter that reliably responds to a slowly changing environment, while effectively ignoring fast fluctuations. The sensitive low-frequency response was significantly faster than in predictions arising from our computational modelling, and this discrepancy was resolved by the discovery that two key galactose transcripts possess half-lives that depend on the carbon source. Finally, to explore how induction characteristics affect frequency response, we compare two S. cerevisiae strains and show that they have the same frequency response despite having markedly different induction properties. This suggests that although certain characteristics of the complex networks may differ when probed in a static environment, the system has been optimized for a robust response to a dynamically changing environment.

SUBMITTER: Bennett MR

PROVIDER: S-EPMC2654342 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Metabolic gene regulation in a dynamically changing environment.

Bennett Matthew R MR Pang Wyming Lee WL Ostroff Natalie A NA Baumgartner Bridget L BL Nayak Sujata S Tsimring Lev S LS Hasty Jeff J

Nature 20080730 7208

Natural selection dictates that cells constantly adapt to dynamically changing environments in a context-dependent manner. Gene-regulatory networks often mediate the cellular response to perturbation, and an understanding of cellular adaptation will require experimental approaches aimed at subjecting cells to a dynamic environment that mimics their natural habitat. Here we monitor the response of Saccharomyces cerevisiae metabolic gene regulation to periodic changes in the external carbon source ...[more]

PMID: 18668041

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Project description:The existence of dynamic cellular phenotypes in changing environmental conditions is of major interest for cell biologists who aim to understand the mechanism and sequence of regulation of gene expression. In the context of therapeutic protein production by Chinese Hamster Ovary (CHO) cells, a detailed temporal understanding of cell-line behavior and control is necessary to achieve a more predictable and reliable process performance. Of particular interest are data on dynamic, temporally resolved transcriptional regulation of genes in response to altered substrate availability and culture conditions. In this study, the gene transcription dynamics throughout a 9-day batch culture of CHO cells was examined by analyzing histone modifications and gene expression profiles in regular 12- and 24-hr intervals, respectively. Three levels of regulation were observed: (a) the presence or absence of DNA methylation in the promoter region provides an ON/OFF switch; (b) a temporally resolved correlation is observed between the presence of active transcription- and promoter-specific histone marks and the expression level of the respective genes; and (c) a major mechanism of gene regulation is identified by interaction of coding genes with long non-coding RNA (lncRNA), as observed in the regulation of the expression level of both neighboring coding/lnc gene pairs and of gene pairs where the lncRNA is able to form RNA-DNA-DNA triplexes. Such triplex-forming regions were predominantly found in the promoter or enhancer region of the targeted coding gene. Significantly, the coding genes with the highest degree of variation in expression during the batch culture are characterized by a larger number of possible triplex-forming interactions with differentially expressed lncRNAs. This indicates a specific role of lncRNA-triplexes in enabling rapid and large changes in transcription. A more comprehensive understanding of these regulatory mechanisms will provide an opportunity for new tools to control cellular behavior and to engineer enhanced phenotypes.

Dataset Information

Metabolic gene regulation in a dynamically changing environment.

Publications

Metabolic gene regulation in a dynamically changing environment.

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