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bioRxiv · 10.1101/2022.03.08.483537

BMAL1 and MEX3A co-regulate intestinal stem cell succession

Chang, F.-P.·Wang, C.-K.·Chou, Y.-C.·Chen, T.-J.·Wu, Y.-W.·Sridharan, S.·Hsu, P.-H.·Hwang-Verslues, W. W.
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Abstract

Chemotherapeutic agents, such as 5-fluorouracil (5-FU), often induce intestinal mucositis due to toxicity to rapidly dividing intestinal stem cells (ISCs). Drug delivery at different times of day can alter 5-FU toxicity; however, the underlying biology is unclear. We found that homeostasis and succession between two ISC types, fast proliferating Lgr5+ crypt base columnar (CBC) cells and stress-resistant +4 cells (Bmi1+), are controlled by the circadian clock transcription factor BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A via both direct transcriptional regulation and post-transcriptional control of Lgr5 mRNA stability. Bmal1 knockout in Lgr5+ CBCs reduced MEX3A expression and CBC numbers but increased Bmi1 expression in the crypts. Timing 5-FU delivery when crypt cells had low Lgr5 but peak level of Bmi1 protected ISCs from apoptosis. Together, these findings identify a novel role of BMAL1 in ISC homeostasis and provide a biological explanation for chronotherapeutic chemoprotection.

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Chang, F.-P., Wang, C.-K., Chou, Y.-C., Chen, T.-J., Wu, Y.-W., Sridharan, S., Hsu, P.-H., Hwang-Verslues, W. W.. 2022-03-10. BMAL1 and MEX3A co-regulate intestinal stem cell succession. https://doi.org/10.1101/2022.03.08.483537

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