FBS Colloquia No.194Synaptic Plasticity Group

The methyl cycle in health and disease: insights from the clock

The methyl cycle is an ancestral biochemical pathway in which methionine is used for the synthesis of S-adenosylmethionine, the methyl donor co-substrate in transmethylation reactions. It is sensitive to the metabolic state of the organism and has a wide impact on gene expression and function via methylation of nucleic acids, proteins, phospholipids and small molecules. We have shown that inhibiting the methyl cycle causes the circadian clock to slow down in mouse and human cells, and its inhibition in the mouse brain in vivo is sufficient to elicit changes in circadian behaviour. We linked this inhibition to the decrease in the N6- methylation of internal adenosines within messenger RNA (m6A) and identified methylation sites in clock gene transcripts. More recently, we have shown that the expression of Casein Kinase 1 Delta (CK1D) is regulated by m6A. When methylation of this transcript is inhibited or prevented by mutation, the translation of two uncharacterised spliced isoforms CK1D1 and CK1D2 increases, accompanied with the elongation of the circadian period. In contrast to previous reports on the canonical isoform CK1D1, an increase in CK1D2 activity stabilises the target phosphoprotein PER2, leading to period elongation. Further investigations on the link between the methyl cycle and the circadian clock are under way.