bioRxiv : the preprint server for biologyAug 20, 2026

The body’s daily clock controls gut lining cell development through rhythmic NOTCH/Hes1 signals

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 21, 2026

Abstract

NOTCH signaling is identified as a pathway regulated by circadian rhythms in intestinal epithelial cell differentiation.

Circadian rhythms influence cellular processes, including the proliferation of intestinal epithelial cells.
RNA-Seq analysis reveals that NOTCH signaling is crucial for the differentiation of these cells and is under circadian control.
In mouse enteroids, oscillations of a NOTCH reporter exhibit different patterns depending on cell stemness.
Single-cell analysis shows significant variation in the timing of Hes1 oscillations among individual cells.
Circadian rhythms appear to affect the population dynamics of Hes1-expressing cells.
Paneth cell numbers fluctuate with the circadian cycle, indicating that circadian regulation of Hes1 influences IEC composition.

Simplified

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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The body’s daily clock controls gut lining cell development through rhythmic NOTCH/Hes1 signals

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