Timely sleep for healthy cells

By Minghao Chia
CRUK London Research Institute, UK

This summary was highly commended by the judges for Access to Understanding 2015

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Many of us may have experienced headaches and drowsiness when our sleep-wake schedules are disrupted by cross-continental air travel or by working night shifts. How can we explain and manage these symptoms? Derk-Jan Dijk and colleagues provide an answer by finding out what happens in our cells when we mistime our sleep.

Our master clock

Most of our cells possess internal clocks that cause fluctuations in cell activities in a roughly twenty four hour cycle. These cycles are called “circadian rhythms” and are coordinated by a “master clock” in our bodies. Our master clock is a network of neurons called the suprachiasmatic nuclei in a brain region called the hypothalamus. It acts like a conductor in an orchestra, ensuring that different members keep to the same tempo. Our master clock sets its time according to light information and communicates with our cells by directing the production of a blood-borne chemical messenger called melatonin. Darkness stimulates melatonin production and triggers sleepiness while brightness inhibits this process and rouses us from slumber. Staying awake when it reads night time on our master clocks creates a mismatch that can cause headaches and drowsiness.

Studying how mistimed sleep affects cell activity

Derk-Jan Dijk and colleagues mimicked the effects of mistimed sleep in healthy volunteers. The scientists controlled the timing of their master clocks by exposing the volunteers to dim light during scheduled waking times and complete darkness during sleep. This ensured that melatonin levels rose and fell at roughly the same times for each day. All volunteers were subjected to a sleep-wake cycle of twenty eight hours where sleep was delayed by four hours for three consecutive days. At first, their sleep coincided with night time on their master clocks when melatonin levels were rising. After three days of delayed sleep, the volunteers now experienced a twelve hour difference between their sleeping times and the time on their master clocks.

To determine how the volunteer’s cells responded to mistimed sleep, the researchers studied molecules within the cell called ribonucleic acids (RNAs). RNAs are messages relaying instructions from our genes to make different proteins which determine cell activity. The researchers isolated RNAs from two sets of blood samples drawn at periodic intervals. One set of samples was collected initially when the volunteer’s sleep-wake cycles matched the timings of their master clocks. The other set was collected after three days when the volunteers had mistimed sleep-wake cycles. By comparing the relative amounts of different RNAs collected in both sets of samples, the researchers obtained snapshots of cellular function that varied with time or with sleep condition.

What was discovered?

The researchers examined the RNA messages whose levels normally cycle in a twenty four hour period. RNAs representing genes involved in wound healing and immunity normally peak in the day, while those involved in protein production peak at night. The researchers found that mistimed sleep caused a greater than six-fold decrease in the number of cycling RNAs. Compared to a previous study, mistimed sleep deregulated the rhythms of more RNAs than insufficient sleep! By interfering with the timely regulation of RNAs, mistimed sleep could impair our cell’s abilities to adapt to the different needs of our bodies during day-time and night-time.

The researchers also demonstrated that timely sleep cooperates with our master clocks, directing our cells to enhance protein production at night. When the volunteers timed their sleep-wake cycles with their master clocks, the levels of RNAs representing genes involved in protein production peaked at night and fell during the day. Mismatching their sleep-wake cycles with their master clocks disrupted the rhythmic production of these RNAs and reduced their levels at night. This suggests that timely sleep could be important for refreshing our body’s protein pools after a day’s work.

Why does this matter?

This study sheds more light on the RNAs that are controlled by our master clocks and by our sleep-wake cycles, providing the foundation for more detailed investigations into the biological functions of sleep.

Furthermore, the results demonstrate that timely sleep is necessary for regulating when different genes are active or inactive. It appears that we cannot compensate for mistimed sleep by merely sleeping for longer periods. This could be why we still feel inadequately rested after sleeping if we have recently done a night shift or have taken a long distance flight. Our sleep-wake cycles must be coordinated with the rhythm of our master clocks for optimal cellular function. Controlled exposure to light can synchronise sleep-wake cycles with our master clocks and will assist people in recovering from night shifts and jet lag. Since aging and illnesses can disrupt circadian rhythms, these results could inform therapies to improve the quality of life for these people too.

It looks like where sleep is concerned, both quantity and timing matter.

This article describes the research published in:

Mistimed sleep disrupts circadian regulation of the human transcriptome
N. Archer, E. E. Laing, C. S. Möller-Levet, D. R. van der Veen, G. Bucca, A. S. Lazar, N. Santhi, A. Slak, R. Kabiljo, M. von Schantz, C. P. Smith, D.-J. Dijk Proc. Natl. Acad. Sci. USA (2014) 111(6), E682–E691

This article was selected for inclusion in the competition by the Biotechnology and Biological Sciences Research Council.



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