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

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.

>Who will benefit
Methyl metabolism is at the center of many fundamental processes including epigenetic regulation of gene expression, nucleotide metabolism and the cell cycle and protection against reactive-oxygen species (one of the main causes of ageing). Methyl cycle pathologies are well-known, such as hyperhomocysteinemia, causing cardiovascular diseases, and folic acid deficiency, causing anaemia in adults and birth defects in new-borns. In addition, methyl cycle-related metabolism is one of the most common targets of cancer treatment. The methyl metabolism is essential for development and requires essential nutrients such as the amino acid methionine, vitamin B9 (folic acid) and B12. Indeed, it is such an important part of our metabolism that the World Health Organization now recommends a daily intake of at least 0.4 g of folic acid, and an even higher intake for pregnant women. Due to this, virtually all breakfast cereals are enriched in vitamin B9.
Since 2013, mRNA methylation has been shown to be essential for cell differentiation, to be involved in the development of cancer, in the function of our biological clock, and in stress response and fear memory. It thus appears that mRNA methylation underlies many fundamental processes that allow our body to function and respond to our environment. Yet, how is mRNA methylation regulated, and what physiological processes it underlies, remain poorly understood.

This research seeks to understand the link between our diet, mRNA methylation and our biological clock, how they regulate each other, and what pathologies occur when this link is disturbed. Discoveries made during this research will interest not only scientists focusing on understanding fundamental questions on how our body work, but will also benefit clinicians and pharmacologists trying to identify new ways to correct pathologies linked to methyl metabolism (e.g. cardiovascular diseases, ageing-related diseases, cancer, anaemia and immunodeficiencies), which will ultimately increase the knowledge in our society, promote drug development, and benefit patients suffering from methylation-related diseases.

Approach to openness: The policy for the dissemination of research results emanating from this fellowship will be open access for all. This will be ensured by making preprints available as soon as the results obtained are significant, reliable and reproducible, and final publications will be in open access journals. Results will be further communicated using social medias.

>How will they benefit
Via the publication of research results and their presentation at (inter)national conferences and laboratories, via the supervision of the next generation of scientists, and via outreach programmes such as lectures in high school or public activities at the Community Festival organized by the University of Manchester, this research will contribute to the nation's culture and academic competitiveness.

The Manchester Academic Health Science Centre is a partnership between the University of Manchester and six NHS Trusts and hospitals to allow rapid translation of research findings into routine public health practice. This is another key feature of the local environment that determined the fellow's choice of the University of Manchester as the host institution. Via this platform, clinical scientists and pharmacologists will directly benefit from the research outputs.

The first two years will see dramatic increase of the fellow's team skills and network thanks to the excellent local and national research environment, with exchange of information sought whenever possible, starting with the creation of an informative webpage about the research being conducted and the people involved. Early In the third year, some concrete outputs should already be available in the form of preprints and/or publications in open access journals. Thereafter, the progressive nature of this proposal will ensure a constant flow of outputs.