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

We uncover a cycling and NF-kappa B-driven lncRNA (named Lnc-UC) that epigenetically modifies transcription of circadian clock gene Rev-erb alpha, thereby linking circadian clock to colitis. Cycling expression of Lnc-UC is generated by the central clock protein Bmal1 via an E-box element. NF-kappa B activation in experimental colitis transcriptionally drives Lnc-UC through direct binding to two kappa B sites. Lnc-UC ablation disrupts colonic expressions of clock genes in mice; particularly, Rev-erb alpha is down-regulated and its diurnal rhythm is blunted. Consistently, Lnc-UC promotes expression of Rev-erb alpha (a known dual NF-kappa B/Nlrp3 repressor) to inactivate NF-kappa B signaling and Nlrp3 inflammasome in macrophages. Furthermore, Lnc-UC ablation sensitizes mice to experimental colitis and abolishes the diurnal rhythmicity in disease severity. Mechanistically, Lnc-UC physically interacts with Cbx1 protein to reduce its gene silencing activity via H3K9me3, thereby enhancing Rev-erb alpha transcription and expression. In addition, we identify a human Lnc-UC that has potential to promote Rev-erb alpha expression and restrain inflammations.