Dissecting the Rev-erbα Cistrome and the Mechanisms Controlling Circadian Transcription in Liver

Abstract

Circadian clocks maintain whole-body metabolic homeostasis by coordinating rhythmic gene expression in multiple tissues. Core clock regulators sustain their own oscillation and confer expression rhythmicity on clock-controlled genes (CCGs). Our unbiased examination of enhancer RNA (eRNA) transcription around the clock in mouse liver identified functional enhancers of circadian genes driven by phase-specific transcription factors (TFs). Rev-erbα emerged as a primary driver of circadian enhancers, leading to oscillating gene expression in opposite phases through direct and indirect regulation. Among Rev-erbα target genes were core clock components and metabolic CCGs. Oscillation of clock genes was enforced by direct competition between Rev-erbα and RORα for binding to cognate motifs in the genome, whereas metabolic CCGs were governed by recruitment of the NCoR/HDAC3 complex to enhancers where Rev-erbα is tethered by tissue-specific TFs. The DNA sequence–mediated competition between Rev-erbα and RORα ensures consistent clock control across all tissues. In contrast, the tethered binding mechanism is tissue-specific and thus allows Rev-erbα to dictate an epigenomic rhythm tailored to the specific need of that tissue. Therefore, discrete modes of recruitment allow Rev-erbα to link the clock to cell-specific functions, including metabolism.