Methylation of mRNA as a coupling mechanism between diet, metabolism and the circadian clock.

mRNA 甲基化作为饮食、新陈代谢和生物钟之间的耦合机制。

• 批准号: MR/Y003896/1
• 负责人: Jean-Michel Fustin
• 金额: $ 75.06万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY003896%2F1
• 关键词: Methylation; mRNA; coupling; mechanism; between

DNA encodes our genetic information, which is ultimately turned into proteins - the building blocks and functional molecules of our cells. However, DNA must first be "transcribed" into a transient intermediary molecule called messenger RNA (mRNA), which are short-lived copies of individual genes, providing instructions for the production of specific proteins. This additional step allows for fluidity in the expression of certain genes based on the needs of a cell, as hundreds of mRNA copies can be read to produce proteins simultaneously (rather than a single copy in the DNA), and then degraded when no longer needed. Thus, the relative rates of mRNA production and degradation are controlled to govern the responses of our cells. This control can be achieved through the addition of a small chemical group called "methyl" (a chemical reaction called methylation) composed of one carbon atom linked to three hydrogen atoms, at various locations along the mRNA molecule. Despite being fundamental to life, we actually understand very little of the significance of mRNA methylation in adult animals, as deficiencies are lethal during development and embryos do not survive. Over the last few years we have obtained evidence that mRNA methylation not only underlies our body clock that controls our rest/activity cycles, but also regulate the activity of neurons important for motor functions. The exact molecular mechanisms remain to be described, and these investigations are likely to yield interesting new candidate targets for the treatment of movement disorders in humans including Parkinson's disease and essential tremors.A fundamental knowledge gap exists between the dietary origin of methyl groups and their metabolism in our body. Methylation is not just restricted to mRNA, but also affects our DNA, and many proteins, thus representing one of the most common forms of biochemical modifications occurring within the cell. Moreover, all methylations depend on the essential nutrients methionine, vitamins B9 and choline. Deficiencies of these nutrients, as well as mutations in enzymes that uses them, are associated with life-threatening disease including cancer, birth defects, anemia, immunodeficiencies, muscle damages and hepatitis. In the past few years we set out to answer these questions: How is methyl metabolism regulated by our diet? Can the normal feeding/fasting cycles that are controlled by our circadian clock, leading to daily variations in the intake of these nutrients, impact on methyl metabolism and mRNA methylation? And since methyl metabolism underlies our biological rhythms, can disturbed sleep and body rhythms be used as early signs of dietary deficiencies in nutrients related to methyl metabolism? While we provided answers to some of these questions, answers that were published in scientific journals and newspapers in 2022, further work remains to be done to understand how our diet influences our behaviour. A thorough understanding of how methyl metabolism is regulated will provide insights into how deficiencies can be detected and corrected.

DNA对我们的遗传信息进行编码，这些信息最终会转化为蛋白质--我们细胞的构件和功能分子。然而，DNA必须首先被“转录”成一种称为信使RNA(信使RNA)的瞬时中间分子，信使RNA是单个基因的短暂拷贝，为特定蛋白质的生产提供指令。这一额外的步骤允许基于细胞需求的某些基因表达的流动性，因为数百个mRNA拷贝可以被同时读取以产生蛋白质(而不是DNA中的单个拷贝)，然后在不再需要时被降解。因此，信使核糖核酸的产生和降解的相对速率受到控制，以控制我们细胞的反应。这种控制可以通过在信使核糖核酸分子的不同位置添加一个由一个碳原子与三个氢原子相连的名为“甲基”(称为甲基化的化学反应)的小化学基团来实现。尽管是生命的基础，但我们实际上对成年动物的mRNA甲基化的意义知之甚少，因为缺乏在发育过程中是致命的，胚胎不能存活。在过去的几年里，我们已经获得证据表明，mRNA甲基化不仅是控制我们休息/活动周期的生物钟的基础，而且还调节对运动功能至关重要的神经元的活动。确切的分子机制仍有待描述，这些研究很可能为治疗人类运动障碍提供有趣的新候选靶点，包括帕金森氏病和基本颤动。在甲基的饮食来源和它们在我们体内的代谢之间存在着基本的知识差距。甲基化不仅限于mRNA，还影响我们的DNA和许多蛋白质，因此代表了细胞内发生的最常见的生化修饰形式之一。此外，所有的甲基化都依赖于必需的营养物质蛋氨酸、维生素B9和胆碱。这些营养素的缺乏以及使用它们的酶的突变与威胁生命的疾病有关，包括癌症、出生缺陷、贫血、免疫缺陷、肌肉损伤和肝炎。在过去的几年里，我们开始回答这些问题：我们的饮食是如何调节甲基代谢的？由我们的生物钟控制的正常喂养/禁食周期会导致这些营养物质的每日摄入量发生变化，是否会影响甲基代谢和mRNA甲基化？既然甲基代谢是我们生物节律的基础，那么睡眠紊乱和身体节律是否可以作为与甲基代谢相关的营养缺乏的早期迹象呢？虽然我们提供了其中一些问题的答案，并于2022年在科学期刊和报纸上发表了答案，但仍有进一步的工作要做，以了解我们的饮食如何影响我们的行为。彻底了解甲基代谢是如何调节的，将为如何发现和纠正缺陷提供见解。