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

The circadian clock regulates energy metabolism, with REVERBa emerging as a dominant regulator of lipid metabolism. Here, we generate novel mouse models allowing conditional deletion of REVERBa and antibody-independent ChIP-seq analyses (via Halo-REVERBa) to define REVERBa function in liver and white adipose tissue. Global deletion of REVERBa or mutation of its DNA-binding activity drives profound metabolic dysfunction. In contrast, metabolic and transcriptional dysregulation under conditional REVERBa-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 REVERBa are significantly enriched around sites of REVERBa 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 REVERBa in adipose and liver mitigate system-wide changes in energy flux, rather than orchestrate tissue-autonomous lipogenic tone.