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Circadian clock regulates intestinal epithelial cell differentiation via NOTCH/Hes1 oscillations

Goker, S.; Lee, S. S.; Gaizer, B.; Matsu-ura, T.; Tsoi, S.; Wu, G.; Lim, H.-W.; Juhasz, J.; Csikasz-Nagy, A.; Hong, C. I.

2026-07-30 molecular biology
10.64898/2026.07.30.741736 bioRxiv
Show abstract

The circadian clock regulates diverse cellular processes, including intestinal epithelial cell (IEC) proliferation. However, mechanisms regulating clock-dependent IEC differentiation remain unknown. We performed a time course RNA-Seq using the mouse small intestine and identified NOTCH signaling, a key mechanism regulating IEC differentiation, as one of the pathways under the control of circadian rhythms. Using mouse enteroids, we discovered that a NOTCH reporter, Hes1-luciferase, exhibits both ultradian or circadian oscillations depending on the stemness of mouse enteroids. Furthermore, single-cell analysis of Hes1-mCherry revealed that the period of Hes1 oscillations varies widely, but circadian rhythms modulate the number of Hes1-mCherry+ cells in the population. Finally, we show that Paneth cell numbers fluctuate over the circadian cycle, suggesting that circadian clock-regulated Hes1 drives the circadian dynamics of IEC composition. Our study provides a deeper insight into circadian regulation of IEC differentiation, which will be critical for applications of chronotherapies for digestive diseases.

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