specific DNA sequence commonly referred to as RORE due to its interaction with the transcriptional activator Retinoic Acid Receptor-related Orphan Receptor (ROR). This sequence consists of an “AGGTCA” half-site preceded by an A/T sequence.. Rev-Erbα binds in the major groove of this sequence via its DBD domain, which contains two C4-type zinc fingers. Rev-Erbα can repress gene activation as a monomer through competitive binding at this RORE site, but two Rev-Erbα molecules are required for interaction with NCoR and active gene repression. This can occur by two Rev-Erbα molecules binding separate ROREs or as a stronger interaction through binding a response element that is a direct repeat of the RORE (RevDR2). In mice, it has been shown that the N-terminal regulatory domain contains an important site for phosphorylation by casein kinase 1 epsilon (Csnk1e), which aids in proper localization of Rev-Erbα, and furthermore, that this domain is necessary for activation of the gap junction protein 1 (GJA1) gene. Function Circadian oscillator Rev-Erbα has been proposed to coordinate circadian metabolic responses. Circadian rhythms are driven by interlocking transcription/translation feedback regulatory loops (TTFLs) that generate and maintain these daily rhythms, and Rev-Erbα is involved in a secondary TTFL in mammals. The primary TTFL features transcriptional activator proteins CLOCK and BMAL1 that contribute to the rhythmic expression of genes within this loop, notably per and cry. The expression of these genes then act through negative feedback to inhibit CLOCK:BMAL1 transcription. The secondary TTFL, featuring Rev-Erbα working in conjunction with Rev-Erbβ and the orphan receptor RORα, is thought to strengthen this primary TTFL by further regulating BMAL1. RORα shares the same response elements as Rev-Erbα but exerts opposite effects on gene transcription; BMAL1 expression is repressed by Rev-Erbα and activated by RORα. CLOCK:BMAL1 expression activates the transcription of NR1D1, encoding the Rev-Erbα protein. Increased Rev-Erbα expression in turn, represses transcription of BMAL1, stabilizing the loop. The oscillating expression of RORα and Rev-Erbα in the suprachiasmatic nucleus, the principal circadian timekeeper in mammals, leads to the circadian pattern of BMAL1 expression. The occupancy of the BMAL1 promoter by these two receptors is key for proper timing of the core clock machinery in mammals. Metabolism Rev-erbα plays a role in the regulation of whole body metabolism through controlling lipid metabolism, bile acid metabolism, and glucose metabolism. Rev-Erbα relays circadian signals into metabolic and inflammatory regulatory responses and vice versa, although the precise mechanisms underlying this relationship