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