Dysregulation of the circadian clock by external factors disrupts cellular processes and impacts on physiology and human health

摘要

The circadian clock imposes daily rhythms in behaviour, physiology, and metabolism in organisms, which are essential to the temporal regulation of molecular processes in living systems. These endogenous rhythms allow organisms to synchronize to the geophysical time. In mammals, they are accountable for tissue-specific 24-h oscillations in the expression of 40-80% of all protein-coding genes. External factors including light, feeding regimes and sleep-activity cycles can alter circadian rhythms. Perturbations of circadian rhythmicity lead to failures in diverse biological processes with severe implications in disease development, including cancer. In the present study, several methods were investigated and used in human cell lines and tissues in order to determine their circadian phenotypes. To investigate the potential impact of circadian disruption on biological processes we use cellular models together with computational mathematical modelling which can be used to simulate in vitro and in silico diverse cellular scenarios. From the analysis of cancer cell lines, weak and strong oscillator-phenotypes were observed, indicating a cancer-type specific role of the circadian clock. Additionally, cell lines were used to study the effect of external conditions (e.g., temperature) in altering circadian rhythmicity. The experimental results show that circadian patterns of gene expression can be detected using cells from peripheral tissue. Our data suggest that non-invasive, easily applicable methods can be applied to determine endogenous circadian rhythms in human cells, which can facilitate the investigation of the effects of extreme external environments on the circadian clock, especially in astronauts affected by such conditions. Our work highlights the role of our biological clock as a guardian of a healthy physiology, and forewarns to the potential dangers of its dysregulation.