Biological Rhythms - The Importance of Circadian Clock Genes
- Biological rhythms having a 24 hour cycle are known as circadian. These rhythms synchronize various behavioural, biochemical and physiological processes. Parameters such as body temperature, sleeping, feeding and metabolism show rhythmicity. In mammals, the brain plays an important role in controlling and coordinating circadian rhythms.
- The central core of the ‘circadian clock’ is located in the anterior part of the hypothalamus. This clock oscillates over a 24 hour period even in the absence of external factors. Other circadian oscillators present in other parts of the brain and in other organs are referred to as ‘peripheral clocks’.
- The central clock influences the output of many hormones. For example, melatonin peaks at night and is low during the day. In nocturnal animals such as mice, the level of corticosterone peaks at dusk, whilst conversely in diurnal animals (e.g. humans) cortisol peaks at dawn. This prepares the animal for a period of activity and feeding.
Circadian Clock Genes
Significant progress has recently been made in understanding the molecular process responsible for biological rhythmicity. The central control of this is through tr__anscription factors which regulate the expression of circadian clock genes:
Positive regulators: CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Brain-muscle Arnt like 1)
Negative regulators: PERIOD (PER 1,2,3) and CRYPTOCHROME (CRY 1,2)
This core system is linked to the day/night cycle with CLOCK:BMAL being high during daylight and PER:CRY being high during darkness, irrespective of whether an animal is diurnal or nocturnal.
Circadian Rhythm Disorders
Disruption of circadian regulation can affect normal physiological and biochemical function and can lead to disease. This ranges from minor, reversible conditions to severe systemic damage.
- Jet lag often involves disruption of circadian rhythms. Studies have shown that individuals who frequently fly across time zones show cognitive defects.
- Studies on shift workers suggest that the incidence of cancer, psychological illness, diabetes and cardiovascular diseases is higher in these individuals.
- Glucose metabolism is known to be influenced by clock genes. Imbalance may lead to disorders such as obesity and diabetes.
- Immunological processes: core clock genes are expressed in immune cells. Inflammatory substances known as cytokines peak in the early morning in humans and at dusk in rodents. In rheumatoid arthritis, symptoms often peak in the morning. This is consistent with gene expression profiles of pro-inflammatory cytokines.
- Asthma: tends to worsen during the night. Lung function usually has low level circadian rhythm, but in asthmatic patients the circadian rhythm is much higher. Levels of anti-inflammatory agents such as cortisol and epinephrine are low during the night.
- Cell cycle and DNA repair are highly regulated and any disruption can lead to pathological processes such as cancer. Tumor suppressor genes for example are influenced by the core clock genes.
Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. E. Maury, K.Ramsey, J. Bass. Circulation Research. 2010 Feb 19;106(3):447-62.
Circadian rhythms in gene expression: S.Sukumaran, R.Almon, D.DuBois & W.Jusko. Relationship to physiology, disease, drug disposition and drug action. Advanced Drug Delivery Reviews, June 2010