Tissue-selective targeting redefines the mechanism of nuclear receptor Reverbα control over clock and metabolism - ChIP-seq. Tissue-selective targeting redefines the mechanism of nuclear receptor Reverbα control over clock and metabolism - ChIP-seq

The circadian clock regulates energy metabolism, with REVERBα emerging as a dominant regulator of lipid metabolism. Here, we generate novel mouse models allowing conditional deletion of REVERBα and antibody-independent ChIP-seq analyses (via Halo-REVERBα) to define REVERBα function in liver and white adipose tissue. Global deletion of REVERBα or mutation of its DNA-binding activity drives profound metabolic dysfunction. In contrast, metabolic and transcriptional dysregulation under conditional REVERBα-deletion in liver or adipose tissues is limited and does not include expected metabolic targets. Intriguingly, under either tissue-selective or global targeting, hepatic genes de-repressed upon loss of REVERBα are significantly enriched around sites of REVERBα chromatin binding. The dominant mode of REVERBa action is transcriptional repression directed by cis-elements proximal to responsive genes, with no evidence for transcription-factor tethering. Together these studies show that transcriptional actions of REVERBα in adipose and liver mitigate system-wide changes in energy flux, rather than orchestrate tissue-autonomous lipogenic tone.