Introduction: The rotation and revolution of the earth around the sun create days and nights and seasons, and organisms adapted to this environment can survive on the earth. Humans have evolved adaptations to daily rhythms. However, many human pathologies, including complex cardiovascular and psychiatric diseases, exhibit strong seasonality, which is particularly prominent in many infectious diseases. These physiological changes are all related to seasonal and diurnal expression of the genome, especially immune system genes.
In everyone's impression, the general structure of the solar system is flat, and the eight planets orbit the sun. Although the orbits of the eight planets in the solar system are in the same plane as the sun (the plane of the ecliptic), the solar system where the Earth is located is moving all the time. The Sun carries eight planets around the black hole in the Milky Way, and the Earth carries the Moon around the Sun. Thus, the intuitive human experience is day and night and seasons.
Figure 1 Solar system operation diagram from the ecliptic plane (Source: [1])
Figure 2 The real trajectory of the solar system, the sun carries eight planets forward (Source: [1])
Figure 3 Solar system operation diagram seen with the ecliptic plane as a reference object (Source: [1])
Animals on Earth exhibit a range of behavioral and physiological adaptations in different seasons, such as hibernation and changes in coat color in polar animals; Seasonal reproduction, growth, food intake and migratory behavior of mammals. Many human pathologies, including complex cardiovascular and psychiatric diseases, exhibit strong seasonality, which requires genetic answers, but genome-wide studies of circadian / seasonal rhythms are scarce.
On February 6, PLOS Biology published the first comprehensive map of how the transcriptome of human tissues adapts to major circulatory environmental conditions provided by a research team at the Center for Genome Regulation at Pompeu-Fabra University in Spain. The study details how circadian rhythms and cycles affect humans at the molecular level by measuring changes in intracellular gene activity in different types of tissues.
The research team used deep transcriptome data across human tissues generated by the GTEx consortium (16,151 RNA-seq samples from 932 deceased human donors from 46 organizations) to study the transcriptional effects of circadian and circulatory rhythms in unprecedented tissue numbers; Transcriptional measurements of GTEx were performed entirely at the time of the donor's death, so each person had only one measurement data for one point in time; In addition, GTEx metadata only includes the time of day and the season of death, but does not include the actual date, week, or even month of death. This allowed researchers to artificially distinguish between diurnal and cyclical variations; When clustered on many individuals, these randomly distributed "transcriptional snapshots" along time create time trajectories that reproduce diurnal and seasonal transcriptional changes, and as such, they constitute a unique resource for studying such changes.
Figure 4 Day, night and seasonal classification of GTEx samples (Source: [2])
The results found:
01
The testicles are most affected by the season, and the tissues in the chest cavity are greatly affected by day and night
With the exception of the testes, most tissues did not show any deviations in seasonally specific changes in gene expression, which showed a large increase in gene expression in the fall and a decrease in the spring. This finding may reflect seasonal changes in gonadal function. Day and night and seasonal changes are largely uncorrelated. Brain and gonadal tissues show the highest seasonality, while tissues in the chest cavity show stronger circadian regulation. This suggests that genes and tissues are affected differently by diurnal and seasonal changes.
Diurnal changes are more prominent in the liver, lungs, heart, and upper gastrointestinal tract, reflecting the participation of thoracic organs in circadian rhythmic processes; Seasonal changes have the strongest effect on brain regions and testicles, reflecting the role of the brain-gonadotropin axis in regulating physiological responses to seasonal changes. Specifically, chest tissues had the highest number of circadian genes, including the lungs (17.2% of all genes expressed in tissues), the left ventricle of the heart (19.2%), and whole blood (19%), which could explain differences in circadian heart rate and breathing patterns; In contrast, there were fewer salivary glands (0.63%), transverse colon (0.67%), testes (0.66%), and brain (0.86%-7.8%); The stomach is the tissue with the strongest preference during the day, while the skin that is not exposed to the sun is the tissue with the strongest preference at night. In contrast, sun-exposed skin showed a diurnal preference, suggesting that ultraviolet light plays a role in the activation of gene expression.
Fig. 5 Classification of the total number of diurnal genes in human tissues (Source: [2])
02
Discover new genes affected by day and night
The researchers created a list of 445 genes that had consistent diurnal patterns across multiple tissues. The list includes "clock genes" known to play an important role in circadian rhythms and control when humans are awake and active. The expression variation of the clock gene was conserved in baboons and mice, but the clocks of nocturnal mice were reversed. The list also reveals many genes that were previously unknown to change during the diurnal cycle. For example, THRA, a thyroid hormone receptor that peaks at night in 15 different types of human tissue; TRIM22, which is expressed during viral infection, limits the virus's ability to replicate and peaks during the day.
03
Seasonal gene expression is associated with immune function
The researchers found that 1,748 unique genes had consistent seasonal expression patterns across multiple tissues: 308 in spring, 361 in summer, 1,072 in fall, and 322 in winter. Many of these genes are involved in immune function, and their expression is enhanced in autumn and winter, which coincides with the seasonality of viral infections. Some genes are also associated with the activity of hormones in the hypothalamus and pituitary gland, such as pituitary hormone genes peaking in summer.
In addition, genes associated with various diseases have seasonal fluctuations, such as autumn, when the expression of glioma tumor suppressor region gene 1 (GLTSCR1) associated with intellectual disability increases in 16 different types of tissues; During winter, expression of keratin 1 (KRT1) decreases in 24 different types of tissues. KRT1 mutations in mice have been linked to the regulation of the production of abnormal levels of proteins in the immune system, as well as abnormal pigmentation in the skin.
04
Seasonal gene expression affects the central nervous system
Seasonal changes can alter the structural arrangement of neurons and other cell types within the central nervous system, with the expression of astrocytes supporting neurons increasing in autumn and winter and generally decreasing in summer. The volume and relative arrangement of brain cells, including neurons, astrocytes, and oligodendrocytes, changes in specific subregions of the brain.
05
Diurnal and seasonal gene expression affects efficacy
Circadian rhythms affect drug efficiency, including changes in target and transporter expression. 91 circadian genes (20%) are currently being targeted by 1,071 different drugs; The 307 seasonal genes (18 percent) were targets for 2,632 different drugs, including 11 cancer drugs targeting 16 genes, cisplatin targeting 15 genes, and one cancer drug still in clinical trials. Each medication can benefit from the correct time of day to do.
This is the first study to expand the understanding of the transcriptional effects of physiological changes associated with the circadian cycle across multiple human tissues, seasonal cycles, providing a significant resource for further study of the effects of diurnal and seasonal changes in the human transcriptome. The potential use of the study is that drugs targeting the circadian gene may be adjusted to be administered at time-dependent doses, and clinical trials should also consider the circadian and seasonal days in which the trial will be conducted.
Dr Roderic Guigó, co-author of the study, said: "These findings have important implications for specific gene administration targeting specific body parts. For example, the higher the expression of a gene at a particular time of day, the greater the dose required to block its effects. The timing of drug administration can match the diurnal pattern of gene expression. Our findings may also have implications for clinical trials, as the effect of the same drug dose may vary depending on the time of year. ”