Dataset Information

A detailed map of coupled circadian clock and cell cycle with qualitative dynamics validation.

ABSTRACT:

Background

The temporal coordination of biological processes by the circadian clock is an important mechanism, and its disruption has negative health outcomes, including cancer. Experimental and theoretical evidence suggests that the oscillators driving the circadian clock and the cell cycle are coupled through phase locking.

Results

We present a detailed and documented map of known mechanisms related to the regulation of the circadian clock, and its coupling with an existing cell cycle map which includes main interactions of the mammalian cell cycle. The coherence of the merged map has been validated with a qualitative dynamics analysis. We verified that the coupled circadian clock and cell cycle maps reproduce the observed sequence of phase markers. Moreover, we predicted mutations that contribute to regulating checkpoints of the two oscillators.

Conclusions

Our approach underlined the potential key role of the core clock protein NR1D1 in regulating cell cycle progression. We predicted that its activity influences negatively the progression of the cell cycle from phase G2 to M. This is consistent with the earlier experimental finding that pharmacological activation of NR1D1 inhibits tumour cell proliferation and shows that our approach can identify biologically relevant species in the context of large and complex networks.

SUBMITTER: Rougny A

PROVIDER: S-EPMC8114686 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.