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/S031812/1
• 负责人: Jean-Michel Fustin
• 金额: $ 124.22万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS031812%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 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", 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. Our research will seek to understand the functional role of various types of mRNA methylation using genetically-modified mice that can grow normally and healthily into adulthood, and then be "transformed" into mice deficient in mRNA methylation. This will give us the opportunity to study the behaviour and metabolism of animals deficient in mRNA methylations for the first time.One of the main questions to be investigated is whether mRNA methylation underlies our biological clock, a process central to our responses to food, disease and infection. The biological clock that ticks inside virtually every cell in our body relies on a constant flow of mRNA, with genes interlocked in negative transcription-translation feedback loops, meaning their proteins regulate the production of their own mRNAs. We already have data to show that one type of mRNA methylation affects particular components of the biological clock in cell culture, but we do not know what are the consequences of the lack of methylation on the behaviour of the animals related to the biological clock, such as eating and activity rhythms, and synchronization of their rhythms to the light-dark cycle.Another fundamental knowledge gap exists between mRNA methylation and our metabolic state. Methylation is not just restricted to mRNA, but also affects our DNA, and many proteins, thus representing one of the most common forms of chemical modifications occurring within the cell. Usually, methylation is a reversible and dynamic process, but whether mRNA methylation can be dynamically regulated, maybe providing a way by which the cell can rapidly adjust its biology, is still a matter of debate. Interestingly, methylation depends on nutrients such as the essential amino acid methionine and the vitamins B9 and B12. How, if at all, is mRNA methylation regulated by our diet and metabolism? Can the normal rest/activity cycles that are controlled by our circadian clock, impact on mRNA methylation? Is it affected by deficiency in methionine or vitamins B9/B12, contributing to the pathologies that arises from these deficiencies, such as anaemia?The expanding field of epigenetics is already demonstrating that methylation of our DNA can influenced by environmental exposures such as diet and smoking, and the aging process, and the subsequent changes in gene expression have measurable effects on the appearance and progression of disease. It stands to reason that mRNA methylation may be similarly influenced by our lifestyle and environment, and provide opportunities for intervention in certain diseases or metabolic disorders. Only by understanding more about the underlying biology of mRNA methylation will we be able to unlock this potential.

DNA编码我们的遗传信息，最终转化为蛋白质-我们细胞的构建模块和功能分子。然而，DNA必须首先被“转录”成一种称为信使RNA（mRNA）的瞬时中间分子，它是单个基因的短拷贝，为特定蛋白质的产生提供指令。这一额外的步骤允许基于细胞需要的某些基因表达的流动性，因为可以读取数百个mRNA拷贝以同时产生蛋白质（而不是DNA中的单个拷贝），然后在不再需要时降解。因此，mRNA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mRNA分子沿着的不同位置添加一个称为“甲基”的小化学基团来实现，该基团由一个碳原子连接三个氢原子组成。尽管是生命的基础，但我们实际上对成年动物中mRNA甲基化的意义知之甚少，因为在发育过程中缺乏甲基化是致命的，胚胎无法存活。我们的研究将试图了解各种类型的mRNA甲基化的功能作用，使用转基因小鼠，这些小鼠可以正常健康地生长到成年期，然后被“转化”为mRNA甲基化缺陷的小鼠。这将使我们有机会首次研究缺乏mRNA甲基化的动物的行为和代谢。需要研究的主要问题之一是mRNA甲基化是否是我们生物钟的基础，这是我们对食物，疾病和感染反应的核心过程。我们身体中几乎每个细胞内的生物钟都依赖于mRNA的恒定流动，基因在负转录-翻译反馈回路中相互关联，这意味着它们的蛋白质调节它们自己mRNA的产生。我们已经有数据表明，一种类型的mRNA甲基化会影响细胞培养中生物钟的特定组成部分，但我们不知道缺乏甲基化对与生物钟相关的动物行为（如进食和活动节奏）的影响，另一个基本的知识缺口存在于mRNA甲基化和我们的代谢状态之间。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化学修饰形式之一。通常，甲基化是一个可逆的动态过程，但mRNA甲基化是否可以动态调节，可能提供一种方法，使细胞可以快速调整其生物学，仍然是一个有争议的问题。有趣的是，甲基化取决于营养素，如必需氨基酸蛋氨酸和维生素B 9和B12。如果有的话，mRNA甲基化是如何受到我们的饮食和代谢的调节的？由我们的生物钟控制的正常休息/活动周期会影响mRNA甲基化吗？它是否受到蛋氨酸或维生素B 9/B12缺乏的影响，导致这些缺乏引起的病理，如贫血？表观遗传学领域的不断扩大已经证明，我们的DNA甲基化可以受到环境暴露（如饮食和吸烟）以及衰老过程的影响，随后基因表达的变化对疾病的出现和进展有可测量的影响。mRNA甲基化可能同样受到我们的生活方式和环境的影响，并为某些疾病或代谢紊乱提供了干预的机会。只有更多地了解mRNA甲基化的潜在生物学，我们才能释放这种潜力。

项目成果

Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.

• DOI: 10.1038/s41467-020-20572-8
• 发表时间: 2021-01-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lin H;Huang YS;Fustin JM;Doi M;Chen H;Lai HH;Lin SH;Lee YL;King PC;Hou HS;Chen HW;Young PY;Chao HW
• 通讯作者: Chao HW

S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.

S-腺苷-L-氢绿碱水解酶将蛋氨酸代谢与昼夜节律的时钟和染色质重塑联系在一起。

• DOI: 10.1126/sciadv.abc5629
• 发表时间: 2020-12
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Greco CM;Cervantes M;Fustin JM;Ito K;Ceglia N;Samad M;Shi J;Koronowski KB;Forne I;Ranjit S;Gaucher J;Kinouchi K;Kojima R;Gratton E;Li W;Baldi P;Imhof A;Okamura H;Sassone-Corsi P
• 通讯作者: Sassone-Corsi P

Publisher Correction: Methylation deficiency disrupts biological rhythms from bacteria to humans.

出版商更正：甲基化缺陷会扰乱从细菌到人类的生物节律。

• DOI: 10.1038/s42003-020-1031-0
• 发表时间: 2020
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Fustin JM

Excess S-Adenosylmethionine inhibits methylation via catabolism to adenine

过量的 S-腺苷甲硫氨酸通过分解代谢为腺嘌呤抑制甲基化

• DOI: 10.21203/rs.3.rs-934744/v1
• 发表时间: 2021
• 作者: Fukumoto K

Timed exercise stabilizes behavioral rhythms but not molecular programs in the brain's suprachiasmatic clock.

• DOI: 10.1016/j.isci.2023.106002
• 发表时间: 2023-02-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Hitrec, Timna;Petit, Cheryl;Cryer, Emily;Muir, Charlotte;Tal, Natalie;Fustin, Jean-Michel;Hughes, Alun T. L.;Piggins, Hugh D.
• 通讯作者: Piggins, Hugh D.