Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism

Abstract

Nuclear receptor Rev-erbalpha (NR1D1), previously considered to be an orphan nuclear receptor, is a receptor for heme, which promotes transcriptional repression via recruitment of the NCoR-HDAC3 corepressor complex. Rev-erbalpha gene regulation is circadian, and Rev-erbalpha comprises a critical negative limb of the core circadian clock by directly repressing the expression of the positive clock component, Bmal1. Rev-erbalpha also regulates the metabolic gene pathway, thus serving as a heme sensor for coordination of circadian and metabolic pathways.

Figure 1. Rev-erbα coordinates circadian rhythm and metabolic pathways in a heme-dependent mode.

The binding elements of Rev-erbα, called ROREs, are present in core clock genes and also in important metabolic genes. Heme, a physiological ligand of Rev-erbα, promotes recruitment of the NCoR-HDAC3 corepressor complex to Rev-erbα homodimers bound to target genes and enhances Rev-erbα-mediated repression of those target genes. Heme binding to Rev-erbα induces the feedback inhibition of its own biosynthesis.