FLICKR, JULIE VACCALLUZZOHuman volunteers following a 28-hour sleep-wake cycle expressed far fewer genes in a typical circadian cycle, according to a study published today (January 20) in PNAS. And among the genes that showed aberrant expression cycles were those involved in transcription and translation, pointing to mistimed sleep as a major contributor to the physiological effects of shiftwork and jet lag.

“I think that’s quite new and intriguing,” said neurobehavioral geneticist Valter Tucci at the Italian Institute of Technology in Genova, who was not involved in the study. “The shifting the time of sleep has enormous consequences. Just by looking at the genes, we see most profound disruption.”

In the 1930s and ’40s, circadian research pioneer Nathaniel Kleitman found that, when he forced himself to follow a sleep-wake cycle of 28 hours, his body temperature would not fluctuate as much as it did on a normal, 24-hour cycle....

Dijk and his colleagues invited 22 volunteers into their clinical research center for three days, where the participants’ sleeping periods were delayed by four hours each day, until they were sleeping during the daytime. Drawing blood samples at regular intervals and analyzing the transcripts using microarrays, the researchers found that “there was a massive impact on the regulation on the timing of the expression of those transcripts,” said coauthor Simon Archer, a molecular biologist and sleep geneticist at Surrey.

At the beginning of the experiment, nearly 6.5 percent of the participants’ transcripts followed a 24-hour rhythm, consistent with other estimates of circadian gene expression in the literature. But at the end of three 28-hour days, only 1 percent of their genes showed such cyclical expression. “That’s quite a reduction,” Dijk said. “That basically illustrates that the phenomenon of reduced amplitude [of physiological rhythms] when your sleep is mistimed extends to the molecular level.”

The loss of rhythmicity could be attributed to a couple of factors, including an overall reduction in the amplitude of gene expression cycling as well as shifts in the timing of expression, said Archer. “Some shifted, but in a way that meant that they were no longer circadian; some became bimodal.” Both genes that are normally expressed during the day and genes that typically peak at night were disrupted.

Importantly, the body’s master clock—the suprachiasmatic nucleus (SCN) of the hypothalamus—continued to keep time correctly, as evidenced by the consistent 24-hour cycle of melatonin levels in the participants’ blood. “So what we’re starting to see is that some aspects of rhythmicity in some parts of the brain are still intact, but in other parts of the body the rhythmicity is disrupted,” Dijk said. He and others believe that it is this desynchrony among the body’s clocks that may be the root cause of many physiological problems accompanying shiftwork and jet lag.

Looking more closely at which genes had lost their rhythmic expression, Dijk and his colleagues found that many are known regulators of gene expression. Genes involved in transcription, such as RNA polymerase II, and genes involved in translation, like ribosomal proteins and initiation and elongation factors, had lost their 24-hour cycles. Even some core clock genes, including CLOCK and BMAL1, were disrupted. Finally, genes involved in chromatin modification, such as methylases and acetylases, also exhibited decreased rhythmicity.

“There’s a lot of discussion recently about not only the genetics aspect of sleep, but the epigenetic aspect of sleep,” said Tucci, who today published some of his own research on sleep-dependent gene expression in mice, in Philosophical Transactions of the Royal Society B. “I think [sleep homeostasis research] is going in that direction.”

How mistimed sleep elicits such changes in gene expression remains unclear, said Dijk. Moreover, he wonders whether the experimental design—delaying sleep by four hours each day—could have an impact. “We don’t know how it would look like if you would acutely shift sleep,” for example, by 12 hours all at once, he said.

But one thing is clear: forcibly altered sleep patterns have major effects on gene expression. “It’s not by chance that evolution has favored the development of sleep at a particular time,” Tucci said. “Be careful going against what evolution has given us, we might screw up other systems.”

S.N. Archer et al. “Mistimed sleep disrupts circadian regulation of the human transcriptome,” PNAS, doi/10.1073/pnas.1316335111, 2014.

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