The genetics of mammalian circadian order and disorder: implications for physiology and disease

Abstract

Circadian rhythms in mammals are regulated by a master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN), which coordinates rhythmic processes throughout the organism. Circadian clocks are cell autonomous and these cellular clocks are located in SCN neurons as well as in almost every cell in the body. The molecular mechanism of circadian clocks in mammals involves an autoregulatory transcriptional feedback loop involving the positive elements CLOCK and BMAL1, which transcriptionally activate the negative feedback elements period (PER) and cryptochrome (CRY), which inhibit their own transcription by repressing the CLOCK–BMAL1 complex. Post-translational regulation (for example, phosphorylation, acetylation and ubiquitylation) of clock proteins have important roles in regulating the stability, localization and turnover of clock components. The sleep disorder familial advanced sleep phase syndrome (FASPS) has been found to be caused by mutations in two core clock genes, period homologue 2 (PER2) and casein kinase 1 delta (CSNK1D), in humans. There is weak but emerging evidence for allelic variants in clock genes to be associated with diurnal preference, mood disorders, sleep and metabolic disorders. Peripheral circadian oscillators are controlled by signals arising from the SCN and from proximal signals related to feeding behaviour, hormonal signals and body-temperature fluctuations. In addition to their primary role in the generation of circadian rhythms, recent work has shown that circadian clock genes can affect a wide variety of other physiological processes. Emerging examples of circadian regulation of physiological pathways include diverse aspects of cellular metabolism, cell growth and DNA-damage control, xenobiotic responses, and the modulation of behavioural responses to drugs and alcohol. The knowledge that circadian clocks are cell autonomous and distributed throughout the body provide a new perspective to target central as well as peripheral circadian oscillators for therapeutic intervention.