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

由于地球自转，地球上的大多数生物体每天都暴露在光照波动中。一些聪明的陆地动物和植物已经进化出分子钟，这对跟踪和预测每24小时重复一次的现象至关重要。能够预测光的波动对于几个物种在其环境中茁壮成长至关重要。在哺乳动物中，这是通过内部内源性时钟的分层系统来实现的，该系统由位于视交叉上核的主时钟控制，视交叉上核是由数千个细胞组成的大脑的一小部分。我们知道，几乎每个哺乳动物细胞都有一个专门的生物钟，与激素、进食和温度周期等系统信号同步。在分子水平上，生物钟是由十几个基本核心时钟基因的转录-翻译反馈回路编码的，这些基因经过微调，产生近24小时的振荡。许多研究表明，这些昼夜节律振荡对多种生理过程，包括睡眠-觉醒周期，激素分泌和体温的重要性。同时，细胞周期是另一个重要的细胞过程，与昼夜节律钟有相似之处。事实上，在许多细胞中，细胞周期也持续约24小时，周期本身可以被视为一个重复的振荡过程，从一个阶段到另一个阶段，并在每次细胞分裂时再次返回。这项研究提案是基于我们小组最近发表的一项研究结果，我们已经表明，当细胞周期和生物钟共存于同一个细胞时，它们开始相互作用。我们第一次表明，这种相互作用从小鼠到人类都是保守的，而且它主要是由细胞周期对生物钟的作用驱动的。我们还开发了一种新的建模方法，与活细胞显微镜实验结合使用，能够更精确地识别细胞周期如何与生物钟相互作用。虽然我们的研究结果可以解释细胞周期如何与生物钟相互作用，但它仍然是推测性的，并没有解决它如何在分子水平上精确控制生物钟，也没有告诉我们这种相互作用的生理后果。这个发现计划的目标是使用系统和时间生物学方法，结合基因组学和生物信息学来解决这些问题。该提案的多元化背景以及为回答我们的问题而采取的各种创新方法，将是培养未来一代高素质学生和研究助理的理想环境。

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.