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

Lead Research Organisation: The University of Manchester
Department Name: School of Medical Sciences

Abstract

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.

Publications

10 25 50
 
Description S-adenosylmethionine (SAM), a molecule that can be found in our body, is widely available over-the-counter as a dietary supplement believed to improve joints and mental wellbeing. The rationale is that SAM should promote a chemical reaction named "methylation" that is essential for development and health. Against expectations, however, we found that excess SAM is instead catabolized to adenine, a known toxic metabolite that we showed lead to widespread inhibition of methylation, resulting notably in the disruption of biological rhythms. This highlights the toxicity of SAM and calls for regulations of its availability. We also show that, due to this mechanism we have uncovered, SAM could be used as a potential new chemotherapeutic treatment.

Together with collaborators at the University of Bristol, we have found that timed exercise can stabilise the circadian rhythms of animals that are genetically modified to have poor rhythms, potentially revealing the usefulness of such timed exercises in patients suffering from circadian misalignments

On a different part of our project, we have shown that daily intake of the essential nutrients methionine and choline are critical to support our biological rhythms, and that deficiencies of these nutrients reprogramme the biological clock at the gene expression level. These discoveries help us understand how our physiology and behaviour are controlled by our diet. These studies are still in progress but a preprint was published in early 2024.

We have also identified that genetic deficiencies in methyl metabolism causes changes in behaviour, namely tremors and seizures and changes in circadian behaviour, depending on the enzyme that has been inactivated. We have two manuscripts in preparation about these observations.

In our latest project, we have observed that the effects of fasting on the liver transcriptome is sex-dependant, and that females respond to fasting by activating a specific inflammatory process absent in males, and males respond to fasting by activating steroid metabolism.
Exploitation Route The outcomes of this research inform us on the importance of a balanced diet, every day, and on the danger of nutritional supplements and self-medication. For academia, our discoveries increase our knowledge on how our metabolism is controlled by our diet and by key enzymes whose physiological functions were previously unknown, provide potential new avenues for the treatment of many pathologies that have been linked with methyl metabolism including cardiovascular diseases, anemia, cancer and neurological disorders. New collaborations spanning from these discoveries were initiated.
New grant proposals for subsequent work have been submitted to the BBSRC.
Sectors Agriculture

Food and Drink

Healthcare

Pharmaceuticals and Medical Biotechnology

URL https://personalpages.manchester.ac.uk/staff/jean-michel.fustin/
 
Description Design of a new Python pipeline for the analysis of circadian and non-circadian omics time series 
Organisation University of Manchester
Department Faculty of Biology, Medicine and Health
Country United Kingdom 
Sector Academic/University 
PI Contribution As planned by this MRC project plan, we analysed the short-term and long-term effects of fasting on gene expression in the mouse liver, but due to the lack of an appropriate analyses method we decided to reach out to Magnus Rattray, Professor of Computational and Systems Biology at the University of Manchester, to collaborate for the implementation of a new Python tool to analyse time series in gene expression and exon usage, which would provide a holistic way to tease apart circadian and non-circadian changes in gene expression.
Collaborator Contribution As planned by this MRC project plan, we analysed the short-term and long-term effects of fasting on gene expression in the mouse liver, but due to the lack of an appropriate analyses method we decided to reach out to Magnus Rattray, Professor of Computational and Systems Biology at the University of Manchester, to collaborate for the implementation of a new Python tool to analyse time series in gene expression and exon usage, which would provide a holistic way to tease apart circadian and non-circadian changes in gene expression.
Impact The Python tool, accompanied by a publication, will be made available via GitHub.
Start Year 2025
 
Description Communication officer 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I became the Communication Officer of our Centre for Biological Timing and managed/created accounts with X, BlueSky and LinkedIn that are used to communicate not only my own research findings and impact but also those of everybody at our centre and our collaborators. This allows us to reach the general public, potential industries as well as other academics.
Year(s) Of Engagement Activity 2025