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Circadian Phase Can Be Gleaned From Gene Expression Within Skin Cells

NEW YORK (GenomeWeb) – Based on gene expression in the skin, researchers can gauge a person's circadian phase to within a few hours, according to a new study.

Circadian phase can influence the best time for a person to take a particular drug or undergo surgery, but the authors of the current study argue that the current gold-standard approach to assess human circadian phase, the dim-light melatonin-onset assay, is cumbersome and difficult to standardize.

Instead, Cincinnati Children's Hospital Medical Center's John Hogenesch and his colleagues sought to identify gene expression markers from within skin that correspond to circadian phase. They sampled 20 people multiple times during the course of a day, as well as more than 200 other individuals once, to develop a human circadian transcriptome. As they reported today in the Proceedings of the National Academy of Sciences, the researchers teased out a set of biomarkers that could pinpoint circadian phase.

"[W]e showed that human epidermis has a stronger clock than blood and developed a panel of biomarkers that can phase individuals to within three hours from a single sample," the authors wrote in their paper.

The researchers collected epidermis samples every six hours during a 24-hour sampling period from 19 individuals, after excluding one from the study. They uncovered 110 genes whose expression varied rhythmically during that sampling time. The rhythms showed a bimodal distribution, with peaks in the morning and evening.

They likewise analyzed samples of mouse telogen and anagen skin and uncovered 1,280 and 294 circadian genes, respectively, with similar bimodal distributions. Five genes — ARNTL, NPAS2, NR1D2, HLF, and PER2 — exhibited similar expression patterns across all three sample sets, suggesting to the researchers that they might be evolutionarily conserved.

The researchers then expanded their study population and sampled 219 individuals, without respect to the time of day, and compared their gene expression patterns to the individuals sampled multiple times during the course of a day. They noted that clock genes like ARNTL, NPAS2, and CLOCK that are positively correlated and genes like DBP, NR1D1, and PER3 that are negatively correlated remained so in these additional samples. Using the tool CYCLOPS, the researchers were then able to reconstruct the temporal order of those additional samples.

In addition, they uncovered 188 genes that are rhythmically expressed in the human skin at the population level by combining their two sets of samples.

These findings provide an opportunity to develop biomarkers for circadian phase, the researchers said. They first tested the expression of 10 core circadian clock genes in different tissues from mice and humans, including blood and skin, and found that the co-expression of these genes at the population level was strongest within epidermis samples. They trained the ZeitZeiger tool using the CYCLOPS-determined phase for the 219 samples without sampling time and 43 samples with sampling time and uncovered 29 candidate biomarkers.

When they validated these candidate biomarkers in an additional nine people who were sampled at various times of the day, the researchers found the average predicted phase was within three hours of the actual time.

They noted, however, that "[h]ead-to-head comparisons are needed to define the best source of biomarkers for each application of circadian medicine."