Metabolic regulation of the circadian clock
The circadian clock is a biochemical oscillator located throughout the body where it functions autonomously to temporally regulate tissue physiology. It synchronises tissues in the body and its importance is highlighted by the fact that disruptions to circadian rhythms such as shift work and dietary regimens are associated with pathological conditions. Related to alterations in metabolism these conditions include cardiovascular disease, diabetes, and neurodegeneration. Improving our understanding of the molecular mechanisms that drive our circadian rhythms can help us better understand how to prevent these disorders.
Molecular clock and metabolism
At the molecular level, the circadian clock relies on factors that drive the transcription of a large number of clock-controlled genes (CCGs), including genes that govern metabolic homeostasis. At the same time, chromatin dynamics play an essential role in the timing of circadian gene expression and are also influenced by metabolic intermediates. The goal of the MetEpiClock project was to investigate the crosstalk between cellular metabolism, epigenetic dynamics and circadian rhythms. The research was undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme and focused on the metabolism of the essential amino acid methionine. “Our aim was to assess whether the molecular clock could influence important metabolic pathways that, in turn, affect gene expression through epigenetic mechanisms,” explains the MSCA research fellow Carolina Greco.
Metabolic enzymes and circadian control
Methionine has a central impact on physiology that extends beyond initiation of protein synthesis. It functions to regulate epigenetic dynamics, redox balance and phospholipid homeostasis. Researchers studied the circadian expression of key rate-limiting enzymes regulating methionine metabolism. Specifically, they focused on the methionine adenosyltransferase (MAT) enzymes and the SAH hydrolase enzyme (AHCY) that together regulate the methylation potential of the cell. Intriguingly, using a mass spectrometry approach, they discovered that the core clock regulator BMAL1 interacted with AHCY. “This was the first example of a direct interplay between a metabolic enzyme and a core clock protein, and we wished to investigate this further,” emphasises Greco. Through different types of biochemical assays, researchers confirmed the interaction and showed that this occurred at the chromatin level, suggesting that AHCY may contribute to BMAL1-driven circadian transcription. Quite remarkably, they showed that AHCY is required for circadian transcription through the modulation of histone methylation. Inhibition of AHCY activity in mice led to defects in their normal circadian behaviour, corroborating their hypothesis.
Mechanisms of clock regulation and disease
Overall, the MetEpiClock project unveiled a previously unidentified regulatory circuit of circadian control, illustrating the intimate connection between circadian rhythms and metabolic pathways. Results add an additional layer to the known mechanisms of clock regulation indicating that the molecular clock relies on metabolic enzymes as well as chromatin remodelling components. Dissecting the pathways that link circadian regulation, metabolism and epigenetics is expected to provide central insight into the relationship between circadian disruption and disease. The fact that specific components of this coordinated network respond to environmental cues may help explain how shift working, for example, may lead to metabolic disorders. Most importantly, the MetEpiClock results will pave the way towards novel strategies for both dietary and therapeutic interventions.
Keywords
MetEpiClock, circadian clock, circadian rhythms, epigenetic, methionine metabolism, AHCY, BMAL1, methylation
