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

将新陈代谢与衰老联系起来：组蛋白赖氨酸乙酰化的新作用

• 批准号: BB/P00296X/1
• 负责人: Jane Mellor
• 金额: $ 83万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP00296X%2F1
• 关键词: Linking; metabolism; ageing; new; role

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.

健康的衰老受饮食和光/黑暗周期的影响，这些饮食和光/黑暗周期控制细胞内的互连代谢和昼夜节律。我们研究了贝克的酵母，该酵母具有代谢周期，并且年龄类似于人类，并提供了一个可拖动的系统来发现协调周期和衰老的过程。旨在发现改善健康衰老的新方法的研究促进了人们的关注，工作涉及可能支持未来医疗进步的衰老的基本生物学。我们对衰老所涉及的分子过程的许多了解都是来自使用简单的真核生物作为模型生物的工作。此外，衰老所涉及的许多基因和过程在整个进化过程中都是保守的。我们计划研究与基因表达基本水平上衰老有关的新途径，以及细胞代谢状态对衰老的控制。在这个项目中，我们将使用单细胞真核生物，即酵母糖酿酒酵母。酵母在这项工作方面具有许多优势。我们可以在其代谢周期中同步酵母，这意味着我们可以研究具有相同代谢状态的细胞的整个群体。酵母是直接研究代谢对基因表达的影响的唯一系统之一。将基因包装成染色质，这是一种影响基因表达的DNA和蛋白质的复合物。染色质在由细胞的代谢状态驱动的反应中进行化学修饰，从而使基因表达和代谢得到协调。通常认为，这些化学修饰会影响基因表达的第一步，称为转录，DNA中的遗传信息复制到中间分子RNA，然后将其用作合成蛋白质的模板。我们已经发现了染色质和基因表达的最后一步之间的新联系，即RNA分子中携带的遗传信息转化为蛋白质。通过我们研究在酵母中进行化学修饰的特定区域（在其他生物体中不可能）进行化学修饰的能力，使这一发现成为可能。这也使我们能够将染色质的化学修饰部位与酵母的衰老联系起来。该项目的目的是了解染色质如何影响蛋白质和衰老的翻译。细胞的特征，包括其老化的方式受蛋白质控制，特别是在翻译过程中合成的蛋白质量。蛋白质的产生是细胞周期和衰老的核心，并且受饮食/营养的控制，但尚不清楚详细过程。定义这些过程将在未来促进旨在减轻与年龄有关的症状的理性药物设计。例如，由于蛋白质采用的结构缺陷而产生神经退行性条件，导致正常功能和细胞死亡的丧失。通过改变产生的速度，可以缓解有缺陷蛋白的积累，并且在酵母中可以改善细胞的长期生存能力。总而言之，我们在染色质中发现了一种新型的营养依赖性靶标，该靶标控制了蛋白质的产生速度，并提出了剖析方法的准确剖析。这项工作对理解饮食和节奏周期如何影响蛋白质的产生以及与年龄相关的条件背后的分子机制具有重要意义。

项目成果

Antisense transcription-dependent chromatin signature modulates sense transcription and transcript dynamics

反义转录依赖性染色质特征调节有义转录和转录动力学

• DOI: 10.1101/187237
• 发表时间: 2017
• 作者: Brown T

Mapping Human Transient Transcriptomes Using Single Nucleotide Resolution 4sU Sequencing (SNU-Seq)

• DOI: 10.1101/2021.07.14.452379
• 发表时间: 2021-07
• 期刊: bioRxiv
• 作者: Philipp Lorenz;Anna Lamstaes;Harry Fischl;S. Xi;Aksel J Saukko-Paavola;S. Murray;Thomas Brown;Charlotte L. George;A. Furger;Andrew Angel;J. Mellor

Paf1 Has Distinct Roles in Transcription Elongation and Differential Transcript Fate.

• DOI: 10.1016/j.molcel.2017.01.006
• 发表时间: 2017-02-16
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Fischl H;Howe FS;Furger A;Mellor J
• 通讯作者: Mellor J

Global and Gene-specific Transcriptional Responses to Acute Stress

对急性应激的整体和基因特异性转录反应

• DOI: 10.1101/2021.07.16.452657
• 发表时间: 2021
• 作者: Fischl H

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

寒冷诱导的染色质压缩和时钟 mRNA 的核保留重置了昼夜节律

• DOI: 10.1101/2020.06.05.127290
• 发表时间: 2020
• 作者: Fischl H