The Role of the Circadian Clock in the Intestinal Epithelium during Health, Regeneration, and Tumourigenesis

The Earth’s axial rotation subjects its surface to constant periods of light and dark, this is known as photoperiod. Many organisms have adapted their physiology in accordance with this environmental constant by generating 24h rhythms in their physiological functions; these are known as circadian rhythms. Circadian rhythms are controlled by an endogenous time-keeping mechanism known as the circadian clock. Over 40% of the genome in mice and over 80% of the genome in primates has been shown to have 24h rhythms in transcription. The disruption of circadian rhythms through shiftwork, jetlag, or exposure to light at night is associated with many negative health outcomes. The intestinal epithelium is a one-cell layer thick tissue responsible for nutrient absorption and pathogen defence. The intestinal stem cells found at the base of the crypts of Lieberkühn are essential for maintaining the health of this tissue. In this dissertation, I explored how the circadian clock regulates intestinal epithelium during homeostasis as well as during regeneration and carcinogenesis. I found that the circadian clock controls crucial intestinal stem cell functions such as proliferation and self-renewal. I also found that the disruption of the clock leads to an altered regenerative response as well as an increase in tumourigenesis. Additionally, I found that the loss of the clock alters region-specific stem cell behaviour. This research adds to a growing body of literature that highlights the importance of circadian rhythms during health and disease and shows that disruptions to these daily control mechanisms have negative impacts on health