Cytosolic and Transcriptional Cycles Underlying Circadian Oscillations
Michael H. Hastings1 and John S. O'Neill2
1 Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
2 Division of Cell Biology, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
Circadian ( circa - approximately, - dian a day) clocks are the internal pacemakers that drive the daily rhythms in our physiology and behavior that adapt us to the 24-hour world (Duffy et al ., 2011). They thereby maintain temporal coherence in our core metabolism, even when individuals are held in isolation, experimentally deprived of external timing cues such as light-dark (LD) cycles. As a result of this ability of our endogenous circadian system to define internal time and use it to drive daily rhythms, our brains and bodies can be viewed as 24-hour machines, alternating between states of wakefulness and sleep, catabolism and anabolism, growth/repair and physical activity. It is now widely recognized that disturbance of this daily program can carry significant costs for morbidity and even mortality (Hastings et al ., 2003). Some personal insights into this can come from the subjective experiences of jet lag. More insidiously, however, the disturbance of nocturnal sleep, and consequent disaffected mood, loss of mental capacity and social disruption, is a common element of neurodegenerative and psychiatric conditions (Hatfield et al ., 2004; Wulff et al ., 2010; Bliwise et al ., 2011) (This volume, several chapters). Moreover, epidemiological evidence now associates increased risk of cancer as well as cardiovascular and metabolic diseases with extensive experience of rotational shift-work (Knutsson, 1989; Viswanathan et al ., 2007; Huang et al ., 2011) (This volume, Chapter 13 ), a life-style that will inevitably compromise circadian coherence, and which represents a major and growing hazard to public health. Evolution has programmed us to live by a 24-hour day and where genetic, pathological, environmental or social factors drive us against this program, we pay a heavy price. Conversely, the recognition that our body is a 24-hour machine, with different metabolic and physiological states across day and night, provides a route into enhancing therapeutic efficacy by administering medicines on a schedule that maximizes their bioavailability and by targeting disease states at their most critical and vulnerable phases of the day (Levi and Schibler, 2007).
Key to appreciating the role of the circadian clock in both health and illness, and thereby identifying novel therapeutic strategies, is the unravelling of its molecular and cellular bases. Whilst the formal properties of circadian clocks have been understood for over 60 years, and the identification in 1972 of thesuprachiasmatic nucleus ( SCN ) as the brain's principal pacemaker provided a neuroanatomical focus to circadian biology (Weaver, 1998; Chapter 3 ) ( Fig. 1.1 a-e), proper mechanistic understanding of the timing process proved to be elusive. This changed dramatically from the late 1970s onwards, when "circadian clock genes" and their mechanisms of action were identified: firstly in Drosophila , then in Neurospora , and more recently in mouse (Takahashi et al ., 2008). The outcome of these studies was to reveal that an autoregulatory negative feedback oscillator, based on sequential transcriptional and posttranslational processes, lies at the heart of the circadian timepieces of these divergent groups. Even though the molecular components may differ, the "logic" of the mechanism is conserved. But things move on, and there is growing realization that these transcriptionally based clocks do not operate in isolation; rather, they are mutually