Nutrigenomic regulation of one-carbon metabolism and the circadian clock in health and disease

Abstract Methylation of DNA, histones and RNA is central to the regulation of circadian rhythms, yet the biochemical origin of the methyl groups driving these modifications has received comparatively little attention in circadian biology. This review explores the bidirectional crosstalk between the methyl cycle and the mammalian circadian clock. We describe how S-adenosylmethionine-dependent epigenetic and epitranscriptomic modifications constitute essential layers of circadian gene regulation, and how the clock orchestrates the rhythmic expression of one-carbon metabolism enzymes and oscillations in S-adenosylmethionine availability. The direct interaction between the S-adenosylhomocysteine hydrolase and the core clock component BMAL1 at circadian gene promoters emerges as a molecular nexus linking methyl group supply to clock-driven transcription. We further discuss how the methyl cycle occupies a privileged position within the circadian entrainment hierarchy, acting as both a target of nutritional zeitgebers in peripheral tissues and a potential source of metabolic feedback to the central pacemaker, and how dietary perturbation of the methyl cycle disrupts circadian rhythms. Finally, we discuss how this crosstalk is implicated in metabolic liver disease, cancer, neurological disorders and aging. Together, these findings position the circadian clock as a sensitive read-out of nutritional methyl metabolic status, with broad implications for chronobiology and nutrigenomics.