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Structure theorems and the dynamics of nitrogen catabolite repression in yeast.

ABSTRACT: By using current biological understanding, a conceptually simple, but mathematically complex, model is proposed for the dynamics of the gene circuit responsible for regulating nitrogen catabolite repression (NCR) in yeast. A variety of mathematical "structure" theorems are described that allow one to determine the asymptotic dynamics of complicated systems under very weak hypotheses. It is shown that these theorems apply to several subcircuits of the full NCR circuit, most importantly to the URE2-GLN3 subcircuit that is independent of the other constituents but governs the switching behavior of the full NCR circuit under changes in nitrogen source. Under hypotheses that are fully consistent with biological data, it is proven that the dynamics of this subcircuit is simple periodic behavior in synchrony with the cell cycle. Although the current mathematical structure theorems do not apply to the full NCR circuit, extensive simulations suggest that the dynamics is constrained in much the same way as that of the URE2-GLN3 subcircuit. This finding leads to the proposal that mathematicians study genetic circuits to find new geometries for which structure theorems may exist.

SUBMITTER: Boczko EM

PROVIDER: S-EPMC556013 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Structure theorems and the dynamics of nitrogen catabolite repression in yeast.

Boczko Erik M EM Cooper Terrance G TG Gedeon Tomas T Mischaikow Konstantin K Murdock Deborah G DG Pratap Siddharth S Wells K Sam KS

Proceedings of the National Academy of Sciences of the United States of America 20050406 16

By using current biological understanding, a conceptually simple, but mathematically complex, model is proposed for the dynamics of the gene circuit responsible for regulating nitrogen catabolite repression (NCR) in yeast. A variety of mathematical "structure" theorems are described that allow one to determine the asymptotic dynamics of complicated systems under very weak hypotheses. It is shown that these theorems apply to several subcircuits of the full NCR circuit, most importantly to the URE ...[more]

PMID: 15814615

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Project description:In yeast physiology, a commonly used reference condition for many experiments, including those involving nitrogen catabolite repression (NCR), is growth in synthetic complete (SC) medium. Four SC formulations, SCCSH,1990, SCCSH,1994, SCCSH,2005, and SCME, have been used interchangeably as the nitrogen-rich medium of choice [Cold Spring Harbor Yeast Course Manuals (SCCSH) and a formulation in the methods in enzymology (SCME)]. It has been tacitly presumed that all of these formulations support equivalent responses. However, a recent report concluded that (i) TorC1 activity is downregulated by the lower concentration of primarily leucine in SCME relative to SCCSH. (ii) The Whi2-Psr1/2 complex is responsible for this downregulation. TorC1 is a primary nitrogen-responsive regulator in yeast. Among its downstream targets is control of NCR-sensitive transcription activators Gln3 and Gat1. They in turn control production of catabolic transporters and enzymes needed to scavenge poor nitrogen sources (e.g., Proline) and activate autophagy (ATG14). One of the reporters used in Chen et al. was an NCR-sensitive DAL80-GFP promoter fusion. This intrigued us because we expected minimal if any DAL80 expression in SC medium. Therefore, we investigated the source of the Dal80-GFP production and the proteomes of wild-type and whi2Δ cells cultured in SCCSH and SCME. We found a massive and equivalent reorientation of amino acid biosynthetic proteins in both wild-type and whi2Δ cells even though both media contained high overall concentrations of amino acids. Gcn2 appears to play a significant regulatory role in this reorientation. NCR-sensitive DAL80 expression and overall NCR-sensitive protein production were only marginally affected by the whi2Δ. In contrast, the levels of 58 proteins changed by an absolute value of log2 between 3 and 8 when Whi2 was abolished relative to wild type. Surprisingly, with only two exceptions could those proteins be related in GO analyses, i.e., GO terms associated with carbohydrate metabolism and oxidative stress after shifting a whi2Δ from SCCSH to SCME for 6 h. What was conspicuously missing were proteins related by TorC1- and NCR-associated GO terms.

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Structure theorems and the dynamics of nitrogen catabolite repression in yeast.

Publications

Structure theorems and the dynamics of nitrogen catabolite repression in yeast.

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