| First Author | Hunter AL | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 41 | Pages | 25869-25879 |
| PubMed ID | 32989157 | Mgi Jnum | J:296724 |
| Mgi Id | MGI:6468478 | Doi | 10.1073/pnas.2005330117 |
| Citation | Hunter AL, et al. (2020) Nuclear receptor REVERBalpha is a state-dependent regulator of liver energy metabolism. Proc Natl Acad Sci U S A 117(41):25869-25879 |
| abstractText | The nuclear receptor REVERBalpha 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 REVERBalpha in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBalpha-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 Reverbalpha drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBalpha does not repress lipogenesis under basal conditions. REVERBalpha 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 Reverbalpha (-/-) mouse). Repressive action of REVERBalpha in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity. |
