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

Abstract

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