Dataset Information

Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle.

ABSTRACT: Synchronization of biological functions to environmental signals enables organisms to anticipate and appropriately respond to daily external fluctuations and is critical to the maintenance of homeostasis. Misalignment of circadian rhythms with environmental cues is associated with adverse health outcomes. Cortisol, the downstream effector of hypothalamic-pituitary-adrenal (HPA) activity, facilitates synchronization of peripheral biological processes to the environment. Cortisol levels exhibit substantial seasonal rhythmicity, with peak levels occurring during the short-photoperiod winter months and reduced levels occurring in the long-photoperiod summer season. Seasonal changes in cortisol secretion could therefore alter its entraining capabilities, resulting in a season-dependent modification in the alignment of biological activities with the environment. We develop a mathematical model to investigate the influence of photoperiod-induced seasonal differences in the circadian rhythmicity of the HPA axis on the synchronization of the peripheral circadian clock and cell cycle in a heterogeneous cell population. Model simulations predict that the high-amplitude cortisol rhythms in winter result in the greatest entrainment of peripheral oscillators. Furthermore, simulations predict a circadian gating of the cell cycle with respect to the expression of peripheral clock genes. Seasonal differences in cortisol rhythmicity are also predicted to influence mitotic synchrony, with a high-amplitude winter rhythm resulting in the greatest synchrony and a shift in timing of the cell cycle phases, relative to summer. Our results highlight the primary interactions among the HPA axis, the peripheral circadian clock, and the cell cycle and thereby provide an improved understanding of the implications of circadian misalignment on the synchronization of peripheral regulatory processes.

SUBMITTER: Pierre K

PROVIDER: S-EPMC6044315 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle.

Pierre Kamau K Rao Rohit T RT Hartmanshenn Clara C Androulakis Ioannis P IP

Endocrinology 20180401 4

Synchronization of biological functions to environmental signals enables organisms to anticipate and appropriately respond to daily external fluctuations and is critical to the maintenance of homeostasis. Misalignment of circadian rhythms with environmental cues is associated with adverse health outcomes. Cortisol, the downstream effector of hypothalamic-pituitary-adrenal (HPA) activity, facilitates synchronization of peripheral biological processes to the environment. Cortisol levels exhibit su ...[more]

PMID: 29444258

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Project description:The cell cycle and the circadian clock represent major cellular rhythms, which appear to be coupled. Thus the circadian factor BMAL1 controls the level of cell cycle proteins such as Cyclin E and WEE1, the latter of which inhibits the kinase CDK1 that governs the G2/M transition. In reverse the cell cycle impinges on the circadian clock through direct control by CDK1 of REV-ERB?, which negatively regulates BMAL1. These observations provide evidence for bidirectional coupling of the cell cycle and the circadian clock. By merging detailed models for the two networks in mammalian cells, we previously showed that unidirectional coupling to the circadian clock can entrain the cell cycle to 24 or 48 h, depending on the cell cycle autonomous period, while complex oscillations occur when entrainment fails. Here we show that the reverse unidirectional coupling via phosphorylation of REV-ERB? or via mitotic inhibition of transcription, both controlled by CDK1, can elicit entrainment of the circadian clock by the cell cycle. We then determine the effect of bidirectional coupling of the cell cycle and circadian clock as a function of their relative coupling strengths. In contrast to unidirectional coupling, bidirectional coupling markedly reduces the likelihood of complex oscillations. While the two rhythms oscillate independently as long as both couplings are weak, one rhythm entrains the other if one of the couplings dominates. If the couplings in both directions become stronger and of comparable magnitude, the two rhythms synchronize, generally at an intermediate period within the range defined by the two autonomous periods prior to coupling. More surprisingly, synchronization may also occur at a period slightly below or above this range, while in some conditions the synchronization period can even be much longer. Two or even three modes of synchronization may sometimes coexist, yielding examples of birhythmicity or trirhythmicity. Because synchronization readily occurs in the form of simple periodic oscillations over a wide range of coupling strengths and in the presence of multiple connections between the two oscillatory networks, the results indicate that bidirectional coupling favours the robust synchronization of the cell cycle and the circadian clock.

Dataset Information

Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle.

Publications

Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle.

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