A mechanism for robust circadian timekeeping via stoichiometric balance
Abstract Circadian (∼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 th...
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| Format: | Article |
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Springer Nature
2012-12-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/msb.2012.62 |
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| _version_ | 1850179484042395648 |
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| author | Jae Kyoung Kim Daniel B Forger |
| author_facet | Jae Kyoung Kim Daniel B Forger |
| author_sort | Jae Kyoung Kim |
| collection | DOAJ |
| description | Abstract Circadian (∼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. |
| format | Article |
| id | doaj-art-adb2e17c114d4c24b4327a3ff0359444 |
| institution | OA Journals |
| issn | 1744-4292 |
| language | English |
| publishDate | 2012-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-adb2e17c114d4c24b4327a3ff03594442025-08-20T02:18:28ZengSpringer NatureMolecular Systems Biology1744-42922012-12-018111410.1038/msb.2012.62A mechanism for robust circadian timekeeping via stoichiometric balanceJae Kyoung Kim0Daniel B Forger1Department of Mathematics, University of MichiganDepartment of Mathematics, University of MichiganAbstract Circadian (∼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.https://doi.org/10.1038/msb.2012.62biological clockscircadian rhythmsgene regulatory networksmathematical modelrobustness |
| spellingShingle | Jae Kyoung Kim Daniel B Forger A mechanism for robust circadian timekeeping via stoichiometric balance Molecular Systems Biology biological clocks circadian rhythms gene regulatory networks mathematical model robustness |
| title | A mechanism for robust circadian timekeeping via stoichiometric balance |
| title_full | A mechanism for robust circadian timekeeping via stoichiometric balance |
| title_fullStr | A mechanism for robust circadian timekeeping via stoichiometric balance |
| title_full_unstemmed | A mechanism for robust circadian timekeeping via stoichiometric balance |
| title_short | A mechanism for robust circadian timekeeping via stoichiometric balance |
| title_sort | mechanism for robust circadian timekeeping via stoichiometric balance |
| topic | biological clocks circadian rhythms gene regulatory networks mathematical model robustness |
| url | https://doi.org/10.1038/msb.2012.62 |
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