Dataset Information

Molecular architecture of the mammalian circadian clock.

ABSTRACT: Circadian clocks coordinate physiology and behavior with the 24h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcriptional and post-transcriptional mechanisms to impart temporal control onto mammalian physiology. Understanding the way in which biological rhythms are generated throughout the body may provide avenues for temporally directed therapeutics to improve health and prevent disease.

SUBMITTER: Partch CL

PROVIDER: S-EPMC3946763 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Molecular architecture of the mammalian circadian clock.

Partch Carrie L CL Green Carla B CB Takahashi Joseph S JS

Trends in cell biology 20130801 2

Circadian clocks coordinate physiology and behavior with the 24h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcription ...[more]

PMID: 23916625

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Project description:In mammals, most cells in the brain and peripheral tissues generate circadian (?24 h) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the population mean of cells' intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important because the SCN must entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression in the intracellular feedback loop plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g., oligomer- or phosphorylation-based repression), as widely assumed in previous mathematical models. Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals, and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms and syncytia. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (?24 h).

Dataset Information

Molecular architecture of the mammalian circadian clock.

Publications

Molecular architecture of the mammalian circadian clock.

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