The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation

Area of Science:

• Chronobiology
• Molecular Biology
• Cancer Research

Background:

• Circadian rhythms, regulated by the 24-hour circadian clock, influence hormones, inflammation, and metabolism.
• The role of circadian rhythm disruption in colorectal cancer development is largely unknown.
• The study investigates the nonredundant clock gene Bmal1 in intestinal homeostasis and colorectal cancer using the Apc^min mouse model.

Purpose of the Study:

• To determine if the loss of the circadian clock gene Bmal1 contributes to colorectal cancer.
• To assess the impact of disrupted photoperiod on colorectal cancer development.
• To investigate Bmal1's role in intestinal stem cell signaling and proliferation in the context of colorectal cancer.

Main Methods:

• Utilized Apc^min mice with Bmal1 mutations (full or epithelium-conditional) and disrupted photoperiods to study tumorigenesis.
• Characterized tumors and normal intestinal tissues.
• Employed RNA sequencing on intestinal organoids to analyze circadian transcription rhythms.
• Conducted in vivo and organoid assays to evaluate Bmal1-dependent proliferation and self-renewal.

Main Results:

• Loss of Bmal1 or disrupted photoperiod significantly increased tumor initiation in the Apc^min model.
• The intestinal epithelium's circadian clock regulates key transcripts for regeneration and stem cell signaling.
• Tumors exhibited minimal autonomous or in vivo clock function.
• Apc^min tumors with disrupted clocks showed elevated Hippo signaling activity and reduced Wnt signaling activity.
• Bmal1 deficiency in intestinal organoids led to increased self-renewal, dependent on Hippo signaling.

Conclusions:

• Bmal1 is crucial for regulating intestinal stem cell pathways, including Hippo signaling.
• Disruption of circadian rhythms potentiates colorectal cancer initiation.
• Bmal1 and circadian rhythms are critical regulators of intestinal homeostasis and tumor suppression.