The circadian clock is a biological mechanism present in most living organisms, used to keep track of time and regulate sleep patterns. Normally, it runs on a 24 hour cycle, taking cues from the environment, such as changes in ambient lighting, to help our bodies keep to a relatively constant rhythm of sleep and wakefulness, called a circadian rhythm.
Over the past few decades, much has been learned about the inner workings of these “clocks” – one of the biggest advances being the discovery of Period2 (or PER2), a protein that plays a major role in its timing – yet scientists are still unsure about how our body clocks compensate for changes in temperature and maintain adequate speed.
With the publication of a new study, released on October 1st in Molecular Cell, this question might finally be answered. A team of researchers from Duke-NUS Graduate Medical School in Singapore (Duke-NUS) and the University of Michigan at Ann Arbor shed some light on the way PER2 behaves in the body, as well as clarify how the “clock” adapts to diverse conditions, such as metabolic changes and variations in temperature.
The research team, led by Professor David Virshup from Duke-NUS and Professor Daniel Forger from Michigan, found that the stability of PER2 depends on a process called phosphorylation, whereby phosphates are added at key sites to influence its function, a process not unlike a physical switch.
Whenever the switch is activated, PER2 faces one of two alternative fates: increased stability or increased degradation. Since the “phosphoswitch” is sensitive to changes in temperature and metabolic signals, it can fine-tune the “clock” and make it run on time regardless of changes in the environment.
The mystery part of this whole affair is why the mechanism doesn’t speed up along with rising temperatures just like most other biochemical reactions. The answer, apparently, is that, sensing the environment heating up, the “phosphoswitch” makes PER2 degrade slower, thus maintaining the proper speed of the “clock”.
“This study sheds light on one of the biggest mysteries of the circadian clock in the last 60 years and has helped to explain some of the basic mechanisms that govern the timing of the clock,” said Dr. Virshup, Director of the Cancer and Stem Cell Biology Programme at Duke-NUS and Professor of Paediatrics at Duke University. “By using both biochemical analysis and mathematical modelling we demonstrated how the core circadian clock keeps to a 24-hour cycle despite temperature changes and metabolic changes.”
Other than providing a mathematical model capable of predicting the behaviour of the circadian clock under different circumstances, the study could also have significant implications for drug developers who work on new pharmaceutical solutions for jet lag, sleep disturbances due to shift work, and possibly even seasonal affective disorder.
The next step for the team will be to test their predictions in an animal model and further explore how phosphates and other substances in our bodies may be important in regulating the circadian clock.