An NF-κB-driven lncRNA orchestrates colitis and circadian clock

Area of Science:

• Molecular Biology
• Chronobiology
• Immunology

Background:

• The circadian clock regulates physiological processes, and its disruption is linked to inflammatory diseases like colitis.
• Nuclear factor-kappa B (NF-κB) signaling is a key driver of inflammation in colitis.

Purpose of the Study:

• To investigate the link between circadian rhythm and colitis by identifying novel regulatory elements.
• To elucidate the role of a newly discovered long non-coding RNA (lncRNA), Lnc-UC, in the interplay between the circadian clock and NF-κB signaling in colitis.

Main Methods:

• Identification and characterization of Lnc-UC, a cycling lncRNA regulated by Bmal1 and NF-κB.
• Analysis of Lnc-UC's epigenetic regulation of the circadian clock gene Rev-erbα.
• Assessment of Lnc-UC's role in experimental colitis models in mice, including gene expression analysis and disease severity scoring.

Main Results:

• Lnc-UC expression is driven by the circadian protein Bmal1 and activated by NF-κB during colitis.
• Lnc-UC epigenetically regulates Rev-erbα transcription by interacting with Cbx1 and reducing H3K9me3.
• Lnc-UC ablation exacerbates experimental colitis, blunts Rev-erbα diurnal rhythm, and sensitizes mice to the disease.

Conclusions:

• Lnc-UC acts as a crucial molecular link between the central circadian clock and inflammatory responses in the colon.
• Lnc-UC promotes Rev-erbα expression, which represses NF-κB and Nlrp3 inflammasome activity, thereby mitigating colitis.
• A human Lnc-UC homolog suggests conserved mechanisms for regulating inflammation via circadian pathways.