Interaction between the cell cycle and the circadian clock : mechanism and implications.

由于地球自转，我们星球上的大多数生物每天都暴露在光线波动中。一些聪明的陆生动物和植物进化出了分子钟，这对追踪和预测这种每24小时发生一次的现象至关重要。能够预测光线的波动对一些物种在其环境中茁壮成长至关重要。在哺乳动物中，这是通过一个内部内源性时钟的等级系统来完成的，该系统受位于视交叉上核的主时钟的控制。视交叉上核是大脑中由数千个细胞组成的一小部分。我们知道，几乎每一个哺乳动物细胞都有一个专用的生物钟，与包括激素、摄食和温度周期在内的系统信号同步。在分子水平上，生物钟是由转录-翻译反馈回路编码的，这些反馈回路由十几个基本的核心时钟基因组成，经过微调，可以产生近24小时的振荡。许多研究表明，这些昼夜节律振荡对包括睡眠-觉醒周期、激素分泌和体温在内的多种生理过程具有重要意义。与此同时，细胞周期是另一个与生物钟有相似之处的重要细胞过程。事实上，在许多细胞中，细胞周期也持续大约24小时，周期本身可以被视为一个反复出现的振荡过程，从一个阶段进入另一个阶段，然后在每次细胞分裂时再返回。

Most organisms on our planet are exposed to daily light fluctuations due to Earth's rotation on itself. Some clever terrestrial animals and plants have evolved molecular clocks essential to keep track and anticipate this phenomenon recurring every 24 hours. Being able to anticipate light fluctuations is critical for several species to thrive in their environment. In mammals, this is accomplished via a hierarchical system of internal endogenous clocks under the control of the master clock located in the suprachiasmatic nucleus, a tiny portion of the brain composed of thousands of cells. We know that almost every individual mammalian cell possesses a dedicated circadian clock synchronized to systemic signals including hormones, feeding and temperature cycles. At the molecular level, the circadian clock is encoded by transcription-translation feedback loops of a dozen of essential core clock genes fine-tuned to produce near 24 hours oscillations. Many studies have shown the importance of these circadian oscillations for multiple physiological processes including sleep-wake cycles, hormone secretion and body temperature. In parallel, the cell cycle is another important cellular process sharing similarities with the circadian clock. In fact, in many cells the cell cycle also lasts around 24 hours and the cycle itself could be seen as a recurring oscillatory process, going from one phase to another and back again at every cell division. This research proposal is based on the findings reported in a recent publication by our group where we have shown that, when the cell cycle and the circadian clock cohabit in the same cell, they start to interact. We have, for the first time, showed that this interaction is conserved from mouse to human and that it is mostly driven by the action of the cell cycle on the circadian clock. We have also developed a new modeling approach that, used in combination with live-cell microscopy experiments, enable to identify more precisely how the cell cycle interacts with the circadian clock. While our results could explain how the cell cycle interacts with the circadian clock, it remains speculative and does not address how exactly it controls the clock at the molecular level neither it informs us of the physiological consequences of this interaction. The goal of this Discovery proposal is to use systems- and chrono- biology approaches in combination with genomics and bioinformatics to shade some lights on those questions. The diversified context of this proposal as well as the various and innovative approaches taken to answer our questions, would be the ideal environment to foster the future generation of highly-qualified students and research assistants.