Genes involved in circadian rhythm regulation, twice as active in women. How do these influence disease risk?

The processes in the human body operate according to the circadian rhythm, which is based on a complex biological system through which the physiology and behavior of an organism can adapt to the environment. Chronopharmacology it is a field that has been studied for decades, but which is expanding due to the development of new genomic and transcriptomic sequencing technologies that allow the understanding of the phenomenon at the molecular level. These types of data can contribute to the implementation of personalized medicine.

The results of a new study published in Science show that the daily rhythm of gene expression in humans varies with age and sex. The data have important clinical implications as underlying molecular mechanisms are described the personalized choice of the time of day for the administration of medicines. The peculiarities of gene expression associated with the circadian rhythm explain why the incidence of certain common diseases in the population differs between men and women.

A transcriptomic analysis (evaluation of the sets of RNA molecules) was carried out at the level of 46 human tissues, originating from participants within the project Genotype-tissue Expression (GTEx). With the help of a computerized algorithm, an image of the dynamics of gene expression was outlined during 24 hours. Although studies on post-mortem tissues have been carried out with the aim of understanding the circadian rhythm, the new algorithm allows a much larger scale characterization both in terms of the type of samples and their number.

“Biological Clocks” are perfectly synchronized between human tissues, the expression of genes involved in the circadian rhythm being more pronounced in the morning and evening (around 7am/7pm). Metabolic tissues were characterized by increased rhythmicity, while in the case of brain tissue, it was reduced. Although the expression of genes essential for the generation of the circadian rhythm were similar between the sexes, when different tissues were analyzed a different phenotypic expression was observed between men and women.

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GTEx is an NIH project that includes a human tissue bank and database aimed at studying the relationship between genetic variants and how they are expressed in different tissues. Photo source – NIH

In women almost twice as many genes characterized by this “rhythmicity” were identified during 24 hours, with a more pronounced transcriptomic activity compared to men, especially in liver and in the adrenal gland. Transcriptomic changes observed in the liver explain the difference in liver disease incidence between women and men. These observations have pharmacological implications because these genes with increased rhythmicity in the liver are essential for the processes by which the body eliminates xenobiotics (any chemical compound found in the body but not produced by it).

Alsoage is one of the factors that significantly influence the rhythm of daily gene expression. The number of mRNA molecules in elderly donors was 50% lower than in young donors. The rhythmicity was attenuated in the elderly, especially in coronary artery tissue, which could influence cardiovascular risk. A loss of rhythmicity of gene expression associated with the circadian rhythm has been observed for processes such as biosynthesis of cholesterol, synthesis of fatty acids, regulation of glycolysisprocesses that are also altered at the level of smooth muscle tissue in the vascular wall.

By understanding “biological clocks” and the complex relationship between circadian rhythm, sex and age, new strategies can be identified for the diagnosis and treatment of common diseases in the population (eg metabolic diseases, cancer). algorithm presented in this study is public, available to researchers worldwide, and may have further applications in the analysis of human tissue biopsies, and not just from postmortem samples. Further studies are needed to demonstrate causal relationships between the mechanisms that maintain these biological rhythms and human pathology.

Circadian rhythm and chronobiology

Circadian rhythms are finely tuned temporal mechanisms that generate 24-hour rhythms in the cells of all organisms. “Circadian” means in Latin about a day (circa – approximately, dies – day). In addition to the 24-hour circadian rhythm, there are also weekly, monthly, annual biological cycles that constitute the subject of study of chronobiology. These biological clocks allow organisms to respond to daily changes that occur in the environment, optimizing physiological conditions and behaviors.

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In humans, the circadian rhythm includes systems that integrate various environmental and metabolic stimuli to regulate biological activities – sleep/wake cycle, energy metabolism, immune functions, cell proliferation. Disturbance of these rhythms through habits such as sleep deprivation or eating late can cause chronic diseases (obesity, diabetes, cancer, etc.). The biological systems that control a person’s circadian rhythm change with age.

In 2017, the Nobel Prize in Medicine and Physiology was awarded to “uncovering the molecular mechanisms that control the circadian rhythm”. The three laureates demonstrated how the interaction between different genes and the proteins they code for determines molecular variations at the level of each cell.

Photo source – Adobe

Molecular mechanisms involved in the circadian rhythm, new targets in the fight against cancer

Circadian rhythm changes are intensively studied in oncology. Clinical studies have so far demonstrated that the optimal time of administration of chemotherapy or immunotherapy can be chosen according to the time of day to reduce toxicities and maximize the effect of therapy.

As sequencing technologies have evolved, more mechanisms have been identified that elucidate how the circadian rhythm influences the activity of oncogenes and tumor suppressor genes that are involved in cancer development. For example, a study recently published in Nature shows that the migration of malignant cells is strongly influenced by the circadian rhythm, and the process is amplified during sleep. The hypothesis was studied in the case breast cancer. Cells that migrate during the resting period have a high capacity to form metastases, unlike those in the active phase. The results could have a major impact on choosing the optimal time to administer treatment, as well as performing routine tests for tumor progression. Also an explanation for cases of cancer colorectal which appear more and more frequently in young people may be related to changes in the circadian rhythm.

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