Methyl Metabolism and the Clock: An Ancient Story With New Perspectives

Methylation, that is, the transfer or synthesis of a -CH₃ group onto a target molecule, is a pervasive biochemical modification found in organisms from bacteria to humans. In mammals, a complex metabolic pathway powered by the essential nutrients vitamin B9 and B12, methionine and choline, synthesizes S-adenosylmethionine, the methyl donor in the methylation of nucleic acids, proteins, fatty acids, and small molecules by over 200 substrate-specific methyltransferases described so far in humans. Methylations not only play a key role in scenarios for the origin and evolution of life, but they remain essential for the development and physiology of organisms alive today, and methylation deficiencies contribute to the etiology of many pathologies. The methylation of histones and DNA is important for circadian rhythms in many organisms, and global inhibition of methyl metabolism similarly affects biological rhythms in prokaryotes and eukaryotes. These observations, together with various pieces of evidence scattered in the literature on circadian gene expression and metabolism, indicate a close mutual interdependence between biological rhythms and methyl metabolism that may originate from prebiotic chemistry. This perspective first proposes an abiogenetic scenario for rhythmic methylations and then outlines mammalian methyl metabolism, before reanalyzing previously published data to draw a tentative map of its profound connections with the circadian clock.