Tips from the tip of the iceberg

Daily remodelling of histone proteins underlies interactions between circadian clock genes and metabolic genes. This regulatory mechanism could be widespread, affecting other physiological processes.

If you monitor the precise daily onset of wheel-running behaviour in a mouse kept in an environment devoid of time cues, you can predict that, tomorrow, the animal will start running 23.7 hours — not 23.6 hours, not 23.8 hours — from when it started today. This is because, in organisms as diverse as bread mould, fruitflies, mice and humans, a central circadian clock program coordinates multiple behavioural and physiological processes, including movement, sleep and energy balance, on a daily basis, even when the organism is removed from all external time cues such as the daily light–dark cycle. How such circadian processes are regulated at a molecular level has long fascinated scientists. On page 997 of this issue, Alenghat et al.¹ provide a clue: activation of an enzyme that is involved in chemical modification of chromatin (complexes of DNA and histone proteins) is a central point in the regulation of circadian metabolic processes.

Since the 1970s, studies on the anatomy, neurobiology and function of the mammalian circadian clock have focused on a brain region called the suprachiasmatic nucleus, which has a central role in regulating most, if not all, daily behavioural, physiological and cellular rhythms². It emerged that numerous canonical circadian clock genes (such as Clock, Pers, BMAL1 and Crys) are expressed in many central and peripheral tissues, and that, in vitro, the molecular clock could regulate the diurnal transcription of at least 10% of the genes in any given tissue³. These findings led to the realization that the circadian clock is not just central to the overall temporal regulation of behaviour and physiology, but that it perhaps also has a key role in the regulation of many cellular pathways and networks in various tissues and organs.

Particular attention was paid to how the molecular circadian clock affects processes related to energy homeostasis. There were two main reasons for this. First, mutation of a key circadian gene, Clock, leads to obesity and metabolic syndrome — a combination of disorders that increases the risk of diabetes and heart disease⁴. Second, several genes involved in metabolism, including those mediating the formation of fatty tissue and carbohydrate metabolism (such as Rev-erbα, Rorα and Pparα), show reciprocal regulation with core circadian clock genes⁵.

Alenghat and colleagues' results¹ link these 'chronometabolic' molecular interactions to the cyclic regulation of chromatin through histone acetylation. They show that a specific genetic disruption of the interaction between the nuclear receptor co-repressor 1 (Ncor1) and the chromatin-modifying enzyme histone deacetylase 3 (Hdac3), which is activated by Ncor1, leads to aberrant regulation of clock genes and abnormal circadian behaviour. In turn, the oscillatory expression pattern of several metabolic genes is disrupted, leading to alterations in energy balance. The authors find that mice with loss of function of the Ncor1–Hdac3 complex are leaner than normal, showing increased sensitivity to the hormone insulin as a result of increased energy expenditure. So, contrary to the common perception that disruption of normal daily rhythms (for example, in shift workers) is metabolically deleterious, these results indicate that alterations of normal circadian physiology could lead to favourable metabolic changes — changes that could combat diseases of nutritional excess, including cardiometabolic disorders.

The fact that the remarkable temporal features of mammalian life depend on interactions between many circadian clock genes and complex gene networks has become apparent over the past decade. Regulation of circadian processes by modulations in the expression of clock genes and clock-controlled genes through rhythmic changes in histone modifications is also well documented^6,7,8. What the observations of Alenghat and colleagues highlight is not only that temporal regulation of metabolism is crucial for normal energy balance, but also that the activation of Hdac3 by Ncor1 is central to the epigenetic regulation of circadian and metabolic physiology.

The interrelationship between circadian clock genes, metabolic genes and chromatin modification might have profound implications for cardiometabolic diseases and their treatment (Fig. 1). The precise 24-hour temporal organization that enables a mouse to start its routine behaviour every day 23.7 hours later than the day before might also be important for normal physiology at the tissue and organ level, with the clock — like the conductor of an orchestra — keeping all the different behavioural and physiological components in synchrony. And this need for tight temporal control for cardiometabolic function might represent only the tip of the iceberg.

Figure 1: Clock genes in health and disease.

Alenghat et al.¹ find that activation of the chromatin-modifying enzyme Hdac3 by the Ncor1 protein is a key point of interaction between circadian clock genes and metabolic genes. Deregulation of the diurnal chromatin modifications that control the interplay between these two sets of genes could be central to several metabolic disorders, including cardiovascular disease, diabetes and obesity. Given the influence of the circadian clock on several other physiological systems and behaviours, such interactions could be more widespread, involving neurobehavioural genes, for example. Disruption of interactions between these genes and clock genes could cause various neurobehavioural disorders such as insomnia, depression and addiction. Like an iceberg, the observed chronometabolic epigenetic interactions could be providing only a glimpse of the importance of circadian temporal organization for health and disease.

Although numerous studies have looked for molecular links between circadian and metabolic genes and transcriptional regulation⁹, fewer studies have attempted to examine such links between the core circadian clock genes and the regulatory genes and gene networks underlying other physiological systems. For example, the core molecular clock could involve the activity of neurobehavioural genes and also regulate them through epigenetic mechanisms. Indeed, previous findings indicate that animals with mutations in Clock sleep 1–2 hours less each day than do normal animals and show behaviour associated with bipolar disorder^10,11. Mental disorders and addiction might also involve epigenetic mechanisms that alter chromatin structures at specific gene promoter sites^12,13. So, as with an iceberg, whose tip provides only a glimpse (roughly 10%) of what is below the surface, the importance of circadian temporal organization for health and disease could be much more profound than we realize.