Rev-erbα Dynamically Modulates Chromatin Organization to Control Circadian Gene Transcription

Much of mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors (TF) that comprise molecular clocks. Core clock TFs bind to the genome at non-coding enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. Here we demonstrate that circadian gene expression in mouse liver is controlled by rhythmic chromatin interactions between enhancers and promoters within topologically associating domains (TAD). Rev-erbα-, a core repressive TF of the clock, opposes functional loop formation between Rev-erbα-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 corepressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. These loops are stronger and functionally active in the physiological or genetic absence of Rev-erbα.Thus, a repressive arm of the molecular clock operates by rhythmically interrupting enhancer-promoter loops to control circadian gene transcription. We performed in situ Hi-C and ChIP-seq on C57BL/6J mouse livers harvested 12 hours apart, at zeitgeber time 22 (ZT22, 5 AM) and ZT10 (5 PM) and in genetic absence of Rev-erbα to examine whether chromatin interactions and the binding of looping factors change in a circadian manner.