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

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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.