Antibody-independent ChIP-sequencing and liver-targeted deletion redefine REVERBalpha repressor function - RNA-seq

The nuclear receptor REVERBalpha is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. We perform in vivo antibody-independent ChIP-sequencing of endogenously-expressed REVERBalpha, in order to map its cistrome and so define its repressive targets. We find that REVERBalpha binding sites harbour consensus RORE or RevDR2 motifs, and overlap with corepressor complex binding, without over-representation of putative tethering factors. When Reverbalpha is deleted in a hepatocyte-selective fashion, only modest physiological and transcriptional effects are seen, with de-repressed target genes tightly associating with REVERBalpha binding sites. Thus, contrary to previous reports, REVERBalpha does not repress lipogenesis under basal conditions. REVERBalpha control of a more extensive transcriptional programme is revealed only by perturbation (the metabolically abnormal global Reverbalpha-/- mouse, or acutely mistimed feeding), supporting instead a role for this core clock protein in buffering against metabolic challenge.