Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt...

Area of Science:

• Gastroenterology
• Stem Cell Biology
• Chronobiology

Background:

• The intestinal epithelium relies on LGR5+ crypt base columnar (CBC) cells for rapid regeneration and homeostasis.
• While external niche signals regulate CBC self-renewal, intrinsic mechanisms for CBC homeostasis remain poorly understood.

Purpose of the Study:

• To investigate intrinsic regulatory mechanisms controlling LGR5+ CBC homeostasis.
• To identify key molecular players involved in maintaining LGR5 expression within intestinal crypts.

Main Methods:

• Analysis of BMAL1 and MEX3A roles in LGR5 expression.
• Investigating the molecular interactions between BMAL1, MEX3A, and Lgr5 mRNA.
• Assessing the impact of Bmal1 depletion on LGR5+ CBCs, ferroptosis, and +4 ISC markers.

Main Results:

• BMAL1 directly upregulates MEX3A transcription.
• MEX3A stabilizes Lgr5 mRNA, thereby maintaining LGR5 expression.
• Bmal1 depletion reduces LGR5+ CBCs, increases ferroptosis, and promotes +4 ISC marker expression.

Conclusions:

• A BMAL1-centered intrinsic pathway regulates LGR5 expression in intestinal crypt cells.
• This pathway is crucial for maintaining LGR5+ CBC homeostasis and preventing ferroptosis.
• Findings suggest a novel mechanism contributing to intestinal stem cell regulation.