In a recent study, published in the journal PLOS Biology, researchers have investigated the variation of human gene expression over both circadian and, lesser studied, circannual cycles. The work sheds light on how the human transcriptome changes over both daily and seasonal time periods, and poses questions about temporal dosage of certain drugs.
Sleeping through the winter
It is well-known that human behaviours operate on a day-night cycle. Feeding and sleeping times remain relatively constant across the globe. Many studies have now investigated the transcriptional mechanisms behind these 24-hour cycles circadian cycles, showing the existence of day-night genes and altered expression at specific times.
Less studied, however, is the seasonal cycle of gene expression and behaviour. Circannual, or yearly, cycles are commonly observed in other animals who exhibit seasonal preferences for reproduction and growth. Whilst we are all aware of squirrels and hedgehogs hibernating in the winter, we are perhaps less conscious of the human traits that impacted by the seasons. A notable example of this is a heightened expression of immune cells during the winter, in response to the annual transmission of colds and flus.
On the clock
In the first large scale study of human circannual transcriptome changes, the team from Barcelona analysed extensive data from the Genotype-Tissue Expression (GTEx) database. The researchers looked at RNA-Seq data derived from different tissues in over 900 donors; individuals who had passed away at varying times of the day and year. The researchers were able to infer the trajectories of gene expression across both day-night and seasonal cycles.
Figure 1: Image showing the experimental set-up of the study. The image details the number of donors from each time period, excluding those who passed away during what the researchers deemed to be “twilight” hours. Adapted from Wucher et al., 2023.
The team confirmed that, of the roughly 18,000 genes studied, over 12,000 of these were differentially expressed over the day-night cycle in at least one tissue type, similar to results previously observed in non-human primates. Day-night changes were particularly prevalent in lung tissue yet were less common in certain areas of the brain.
As for seasonal changes, 16,000 genes were identified as having differential expression in at least one tissue type across the year. Over 1,700 genes were uniquely expressed in one season, and, as expected, many immune cells were enriched during the winter months.
Overall, the team found that the number of genes and tissues affected by day-night and seasonal cycles were similar, yet the genes and tissues themselves were largely different. For example, seasonal variation was seen to strongly impact the transcriptional profile of the brain.
Time for change?
Whilst the study had certain limitations, such as an inability to properly assess individuals who passed away during the boundary between day-night or different seasons, ultimately it provides the first in-depth atlas of human gene expression changes across the year. The impacts of this are far-reaching, providing an understanding of human behaviours, disease susceptibility and hormonal control. Notably, many of the genes identified as having differential expression across either the 24-hour or 12-month cycle are known drug targets, many of which are implicated in cancer treatment. These results add to an increasing amount of evidence that individuals could benefit from temporal-dependent dosage of medications. Co-author Roderic Guigó highlighted the impact of the findings, stating that “Our findings could also have an impact on clinical trials, as the effect of the same drug dose may change depending on the season of the year.”