Clocks across taxa: Conserved circadian timekeeping mechanisms

地球绕地轴自转导致了环境的日常变化，从地球上最早的生命开始就影响着生物体的新陈代谢和生理机能。一种内源性的计时机制，即生物钟，进化到允许对日常周期进行预测，并驱动昼夜节律，如动物的睡眠-觉醒周期或植物的淀粉合成和降解。“时钟基因”的节律性表达长期以来被认为引起节律性代谢，直到我们最近确定时钟基因节律对于诸如藻类和人类等多种生物的某些代谢节律是必不可少的[1-2]。此外，我们发现代谢节律可以促进全球基因表达节律，将构成“时钟”的范式从仅仅是基因表达网络转变为包括代谢[3]。我们最近在《自然》杂志上报道了细胞内镁离子浓度的昼夜节律作为细胞自主计时机制，决定了单细胞藻类和人类细胞[3]的关键时钟特性。从机制上讲，我们发现这些节律提供了将节律性代谢与生物钟控制的基因表达联系起来的双边反馈。我们发现的新的代谢昼夜节律在真核生物中是保守的，跨越了10亿年的进化。我们研究的一个关键方面是在“比较时间生物学”研究中利用这种保守性。对于这些研究，我们使用实验模型细胞来有效地测试最具刺激性的假设，并产生新的想法，这些想法随后可以转化为更复杂的生物，如植物、哺乳动物或真菌。我们的模型真核生物物种，金黄色葡萄球菌，提供了独特的优势比任何其他细胞类型。这种海藻是单细胞的，包含一个只有约8000个基因的单倍体基因组，细胞结构的复杂性降低。它生长方便，实验上易于处理，现在是一种完善的生物钟模式生物。利用Ostreococcus，我们将解决昼夜节律基因表达周期与最终促进节律细胞生物学的生化机制之间的基本知识差距。成功的候选人将加入我们的团队，并获得高度多样化的培训计划，包括一般分子生物学，组织培养和生物化学技术，以及时间生物学的特定实验设计，广泛的体内荧光素酶成像，化学生物学和藻类转基因方法。

Earth's rotation around its axis causes daily changes to the environment, influencing the metabolism and physiology of organisms since the first life on earth. An endogenous timekeeping mechanism, the circadian clock, evolved to allow anticipation of the daily cycle and drive circadian rhythms such as the sleep-wake cycle in animals or the synthesis and degradation of starch in plants.The rhythmic expression of 'clock genes' was long thought to cause rhythmic metabolism, until we recently established that clock gene rhythms are dispensable for some metabolic rhythms in organisms as diverse as algae and humans [1-2]. Moreover, we found that metabolic rhythms could contribute to global gene expression rhythms, shifting the paradigm of what constitutes 'the clock' from only gene expression networks to include metabolism [3]. We recently reported in Nature that circadian rhythms in the intracellular concentration of magnesium ions act as a cell-autonomous timekeeping mechanism, determining key clock properties both in a unicellular alga and in human cells [3]. Mechanistically, we found that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression.The novel metabolic circadian rhythms we identified are conserved across eukaryotic life, spanning over a billion years of evolution. A key aspect of our research is to use that conservation to our advantage in 'comparative chronobiology' studies. For these studies, we use experimental model cells to efficiently test the most stimulating hypotheses and generate new ideas that can subsequently be translated into more complex organisms such as plants, mammals, or fungi. Our model eukaryotic species, Ostreococcus tauri, offers unique advantages over any other cell type. This marine alga is unicellular, contains a haploid genome of only ~8000 genes, and a cellular structure of reduced complexity. It is convenient to grow, experimentally highly tractable, and now a well-established circadian clock model organism.Using Ostreococcus we will address the fundamental knowledge gap between circadian gene expression cycles on one hand, and the biochemical mechanisms that ultimately facilitate rhythmic cell biology on the other. The successful candidate will join our team and gain a highly diverse training programme in general molecular biology, tissue culture, and biochemistry techniques, as well as specific experimental design for chronobiology, extensive in vivo luciferase imaging, chemical biology, and transgenic approaches in algae.