Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-10, Vol.117 (41), p.25869-25879
• Main Authors: Hunter, A. Louise, Pelekanou, Charlotte E., Adamson, Antony, Downton, Polly, Barron, Nichola J., Cornfield, Thomas, Poolman, Toryn M., Humphreys, Neil, Cunningham, Peter S., Hodson, Leanne, Loudon, Andrew S. I., Iqbal, Mudassar, Bechtold, David A., Ray, David W.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Antibodies; Binding sites; Biological clocks; Biological Sciences; Circadian Clocks; Circadian rhythms; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Deoxyribonucleic acid; DNA; Energy Metabolism; Gene Expression Regulation; Lipid metabolism; Lipids; Lipogenesis; Liver; Liver - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group D, Member 1 - chemistry; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism; Perturbation; Receptors; Tethering
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2005330117

The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of Reverbα drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global Reverbα −/− mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.