Nuclear receptor Rev-erbα: up, down, and all around

Abstract

Rev-erbα is a nuclear receptor that links circadian rhythms to transcriptional control of metabolic pathways. Rev-erbα is a potent transcriptional repressor and plays an important role in the core mammalian molecular clock while also serving as a key regulator of clock output in metabolic tissues including liver and brown adipose tissue (BAT). Recent findings have shed new light on the role of Rev-erbα and its paralog Rev-erbβ in rhythm generation, as well as additional regulatory roles for Rev-erbα in other tissues that contribute to energy expenditure, inflammation, and behavior. This review highlights physiological functions of Rev-erbα and β in multiple tissues and discusses the therapeutic potential and challenges of targeting these pathways in human disease.

Keywords: Rev-erbα; circadian rhythm; metabolism; nuclear receptor; transcriptional regulation.

Figure 1. Binding configurations of Rev-erbα

(A) At single RORE sites, Rev-erbα can inhibit transcription passively by competing for binding with ROR proteins. (B) Two Rev-erbα proteins bound independently to separate RORE motifs can recruit NCoR in a heme-dependent manner. The NCoR complex recruits HDAC3, which deacetylates surrounding histone tails and represses target gene transcription. (C) A Rev-erbα dimer bound to RevDR2 motif can also recruit NCoR, with similar regulatory effects as in (B).

Figure 2. Tissue-specific rhythms and functions of Rev-erbα

Diagram of Rev-erbα circadian expression patterns and regulatory targets, in various tissues.