A biological basis
for the 8-hour workday?
Thursday, April 23,
2009
Time course of gene expression of
24-, 12-, and 8-hour periods. Bright yellow depicts gene expression
twice that of the median level while bright blue depicts expression
less than 50 percent of the median level. The time of peak
expression of 24-hour cycling genes show a roughly equal
distribution over the course of a day. In contrast, peak expression
of both 12-hour peaks correlate with subjective dusk and dawn.
Credit: Michael Hughes, Ph.D, University of Pennysylvania School of
Medicine
The circadian clock coordinates
physiological and behavioral processes on a 24-hour rhythm,
allowing animals to anticipate changes in their environment and
prepare accordingly. Scientists already know that some genes are
controlled by the clock and are turned on only one time during each
24-hour cycle. Now, researchers at the University of Pennsylvania
School of Medicine and the Salk Institute for Biological Studies
found that some genes are switched on once every 12 or 8 hours,
indicating that shorter cycles of the circadian rhythm are also
biologically encoded. Using a novel time-sampling approach in which
the investigators looked at gene activity in the mouse liver every
hour for 48 hours, they also found 10-fold more genes controlled by
the 24-hour clock than previously reported.
This the first report where researchers have found other
periodicities than the 24-hour cycle functioning in a live
animal.
These findings, which appear in the April issue of PLoS Genetics,
have implications for better understanding disruptions to normal
circadian rhythms that contribute to a host of pathologies such as
cardiovascular and metabolic disease, cancer, and aging-related
disorders.
"The principal frequency, which is not a surprise, is the 24-hour
cycle, and it is the most prevalent," says senior author John
Hogenesch, PhD, Associate Professor of Pharmacology in the
Institute for Translational Medicine and Therapeutics at Penn.
"What was a surprise to us – although we set up the experiment to
see exactly this – are the 12-hour and the 8-hour cycles.
To uncover these shorter oscillations, the Hogenesch and Salk team
isolated RNA from the livers of mice every hour for 48 hours.
Microarray analysis showed that more than 3,000 genes were
expressed on a circadian rhythm – which account for approximately
4% of all of the genes expressed in the liver. Additionally, 260
genes were expressed on a 12-hour cycle and 63 genes were expressed
on an 8-hour cycle. The investigators saw similar 12-hour gene
expression patterns in five other tissues.
"There is an obvious biological basis to a 12-hour rhythm,"
Hogenesch says. "The 12-hour genes predicted dusk and dawn. These
are two really, really stressful transitions that your body goes
through and your mind goes through. Anybody who has young children
realizes that they are more likely to cry around those times – and
you're more likely to cry with them." The shift in gene expression
controlled by these harmonics can help an animal prepare for the
behavioral and physiological changes that accompany the shift from
light to dark and back.
"We have less of a handle on the 8-hour rhythms," he says, "but the
fact that we can see them reliably means to me there is the
possibility that there could be a biological basis to an 8-hour
cycle."
Parallel experiments using RNA samples from synchronized tissue
culture cells uncovered only genes that cycled on a 24-hour rhythm
and showed no evidence of the shorter oscillations, suggesting that
some of the timing cues are systemically controlled and some are
controlled by the cell itself.
Feeding appears to control one of the 12-hour gene expression
peaks. Mice consume about 20% of their daily calories right after
they wake at dusk, which is near one gene expression peak. When the
researchers restricted feeding to a different time of day one
12-hour peak disappeared and the other became more pronounced. "We
were left with the autonomously driven circadian protein
transcription – the 24-hour component – which was unshifted by the
feeding change," Hogenesch says.
The high-density time sampling had an additional payoff: The team
gained a sharper picture of the genes controlled by the 24-hour
circadian clock. "We were able to more precisely measure the number
of protein transcripts and the identity of the transcripts than we
were able to with less frequent time sampling.
"The largest previously identified sets included 400 to 500
circadian-controlled genes and now we have 3,000 that are
oscillating in the liver," says Hogenesch. Using improved
statistical methods also led to better accuracy. "We were able to
more precisely say that, for example, the pituitary gland has
10-fold fewer oscillating protein transcripts than the liver, and
cell-autonomous models have 10-fold less than that."
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University of Pennsylvania School of Medicine
Thanks to University of
Pennsylvania School of Medicine for this article.