Linking metabolism to ageing: a new role for histone lysine acetylation

健康衰老受饮食和控制细胞内相互关联的代谢和昼夜周期的光/暗周期的影响。我们研究面包酵母，它有一个代谢周期，衰老与人类相似，为发现协调周期和衰老的过程提供了一个可处理的系统。旨在发现改善健康老龄化的新方法的研究日益引人注目，解决老龄化的基本生物学问题的工作可能成为未来医学进步的基础。我们对与衰老有关的分子过程的大部分知识来自于使用简单的真核生物作为模式生物的工作。此外，许多与衰老有关的基因和过程在进化过程中是保守的。我们计划在基因表达的基础水平上研究与衰老相关的新途径，并通过细胞的代谢状态控制衰老。在这个项目中，我们将使用单细胞真核生物，酵母酿酒酵母。酵母在这项工作中有很多优点。我们可以同步酵母的代谢周期，这意味着我们可以研究具有相同代谢状态的整个细胞群。酵母是唯一可以直接研究代谢对基因表达影响的系统之一。基因被包装在染色质中，染色质是DNA和蛋白质的复合体，影响基因的表达。在细胞代谢状态驱动的反应中，染色质被化学修饰，从而使基因表达和代谢得以协调。一般认为，这些化学修饰影响基因表达的第一步，即转录，将DNA中的遗传信息复制到中间分子RNA上，然后将其用作合成蛋白质的模板。我们发现了染色质与基因表达的最后一步，即RNA分子中携带的遗传信息转化为蛋白质之间的新联系。这一发现之所以成为可能，是因为我们有能力研究染色质的特定区域，这些区域在酵母中经历了化学修饰，而在其他生物中是不可能的。这也使我们能够将染色质上的化学修饰的特定位点与酵母的老化联系起来。这个项目的目的是了解染色质如何影响蛋白质的翻译和衰老。细胞的特征，包括它如何老化，是由蛋白质控制的，特别是在翻译过程中合成的蛋白质的数量。蛋白质的产生是细胞周期和衰老的核心，并受饮食/营养物质的控制，但详细的过程尚不清楚。确定这些过程将有助于未来合理的药物设计，旨在减轻年龄相关疾病的症状。例如，神经退行性疾病是由于蛋白质所采用的结构出现缺陷，导致正常功能丧失和细胞死亡。缺陷蛋白的积累可以通过改变它们产生的速度来减轻，在酵母中，这可以提高细胞的长期生存能力。总之，我们已经在染色质中发现了一种新的营养依赖靶标，它控制着蛋白质的产生速度，并建议详细分析这是如何实现的。这项工作对于理解饮食和节律周期如何影响蛋白质产生以及年龄相关疾病背后的分子机制具有重要意义。

Healthy ageing is influenced by diet and light/dark cycles that control the interconnected metabolic and circadian cycles within cells. We study baker's yeast, which has a metabolic cycle and ages similarly to humans, providing a tractable system to discover the processes that coordinate cycles and ageing. Research aimed at discovering new ways of improving healthy ageing is rising to prominence, with work addressing the basic biology of ageing likely to underpin future medical advances. Much of our knowledge of the molecular processes involved in ageing has come from work using simple eukaryotes as model organisms. Furthermore, many of the genes and processes involved in ageing are conserved across evolution. We plan to investigate a new pathway linked to ageing at the fundamental level of gene expression, and the control of ageing by the metabolic state of the cell. In this project we will use a single-cell eukaryote, the yeast Saccharomyces cerevisiae. Yeast has many advantages for this work. We can synchronize yeast in their metabolic cycle meaning that we can study whole populations of cells with identical metabolic states. Yeast is one of the only systems in which it is possible to directly study the effect of metabolism on gene expression. Genes are packaged into chromatin, a complex of DNA and protein that influences gene expression. The chromatin is chemically modified in a reaction driven by the metabolic state of the cell, allowing gene expression and metabolism to be coordinated. It is generally believed that these chemical modifications influence the first step of gene expression, known as transcription, the copying of the genetic information in the DNA to the intermediate molecule RNA, which the then used as a template for the synthesis of proteins. We have discovered a new link between the chromatin and the last step of gene expression, the translation of the genetic information carried in RNA molecules into protein. This discovery was made possible by our ability to study particular regions of the chromatin that undergo chemical modifications in yeast, not possible in other organisms. This also enabled us to link this particular site of chemical modification on the chromatin to ageing in yeast. The purpose of this project is to understand how the chromatin influences translation of proteins and ageing. The characteristics of a cell, including how it ages, are controlled by proteins, in particular the amount of protein synthesized during translation. The production of proteins is central to cellular cycles and ageing, and is controlled by diet/nutrients, but the detailed processes are not understood. Defining these processes will contribute in the future to rational drug design aimed at alleviating symptoms of age-related conditions. Neurodegenerative conditions, for example, arise due to defects in the structures adopted by proteins, causing loss of normal function and cell death. The accumulation of defective proteins can be alleviated by altering how fast they are produced, and in yeast this leads to improved long-term viability of cells. In summary, we have discovered a novel nutrient-dependent target in chromatin that controls how fast proteins are produced and propose to dissect exactly how this is achieved. This work has important implications for understanding how diet and rhythmic cycles influence protein production and the molecular mechanisms behind age-related conditions.