A mechanism for robust circadian timekeeping via stoichiometric balance

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Circadian (similar to 24 h) timekeeping is essential for the lives of many organisms. To understand the biochemical mechanisms of this timekeeping, we have developed a detailed mathematical model of the mammalian circadian clock. Our model can accurately predict diverse experimental data including the phenotypes of mutations or knockdown of clock genes as well as the time courses and relative expression of clock transcripts and proteins. Using this model, we show how a universal motif of circadian timekeeping, where repressors tightly bind activators rather than directly binding to DNA, can generate oscillations when activators and repressors are in stoichiometric balance. Furthermore, we find that an additional slow negative feedback loop preserves this stoichiometric balance and maintains timekeeping with a fixed period. The role of this mechanism in generating robust rhythms is validated by analysis of a simple and general model and a previous model of the Drosophila circadian clock. We propose a double-negative feedback loop design for biological clocks whose period needs to be tightly regulated even with large changes in gene dosage. Molecular Systems Biology 8: 630; published online 4 December 2012; doi:10.1038/msb.2012.62
Publisher
NATURE PUBLISHING GROUP
Issue Date
2012-12
Language
English
Article Type
Article
Keywords

REV-ERB-ALPHA; NEGATIVE FEEDBACK LOOP; GENE-EXPRESSION; CLOCK FUNCTION; SUPRACHIASMATIC NUCLEUS; CRYPTOCHROME PROTEINS; BIOCHEMICAL NETWORKS; CELLULAR CLOCKS; OSCILLATOR; PHOSPHORYLATION

Citation

MOLECULAR SYSTEMS BIOLOGY, v.8

ISSN
1744-4292
DOI
10.1038/msb.2012.62
URI
http://hdl.handle.net/10203/203043
Appears in Collection
MA-Journal Papers(저널논문)
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