Nuclear hormone receptors for heme: REV-ERBalpha and REV-ERBbeta are ligand-regulated components of the mammalian clock

Abstract

The nuclear hormone receptors (NHRs), REV-ERBalpha and REV-ERBbeta, regulate a number of physiological functions including the circadian rhythm, lipid metabolism, and cellular differentiation. These two receptors lack the activation function-2 region that is associated with the ability of NHRs to recruit coactivators and activate target gene transcription. These NHRs have been characterized as constitutive repressors of transcription due to their lack of an identified ligand and their strong ability to recruit the corepressor, nuclear receptor corepressor. Recently, the porphyrin heme was demonstrated to function as a ligand for both REV-ERBs. Heme binds directly to the ligand-binding domain and regulates the ability of these NHRs to recruit nuclear receptor corepressor to target gene promoters. This review focuses on the physiological roles that these two receptors play and the implications of heme functioning as their ligand. The prospect that these NHRs, now known to be regulated by small molecule ligands, may be targets for development of drugs for treatment of diseases associated with aberrant circadian rhythms including metabolic and psychiatric disorders as well as cancer is also addressed.

Fig. 1.

Comparison of the Orphan NHRs, REV-ERBα and REV-ERBβ, to the Drosophila melanogaster E-75 DBD, DNA-binding domain. Numbers indicate amino acids. Letters A–F refer to the domain structure common to most NHRs as described in the text. dE75, Drosophila melanogaster E-75.

Fig. 2.

Mechanism of the Cellular Circadian Oscillator The top portion of the figure illustrates the oscillations in Bmal1/Clock and Per/Cry and RORα/REV-ERBα during the 24-h cycle. The lower portion of the figure illustrates the molecular mechanism responsible for creation of the oscillation. The roles of NHRs, RORα, and REV-ERBα are highlighted in this figure.

Fig. 3.

Model Illustrating the Proposed Mechanism for Heme Modulation of REV-ERB Activity REV-ERB functions as a receptor for heme. REV-ERB recognizes and binds specific DNA sequences known as RevREs in the promoter regions of its target genes. Heme binds directly to the LBD of REV-ERB and increases the affinity of the receptor for the corepressor NCoR. When NCoR is recruited to the promoter by REV-ERB, the gene is repressed due to the histone deacetylase activity that is associated with the NCoR/histone deacetylase complex. Modulation of REV-ERB target genes is associated with regulation of physiological functions such as lipid metabolism, circadian rhythm and cellular differentiation. DBD, DNA-binding domain.

Fig. 4.

Examples of Ligands for NHRs Heme is a ligand for REV-ERBα and REV-ERBβ, T₃ is a ligand for the thyroid hormone receptor, 1,25-dihydroxyvitamin D₃ is a ligand for the vitamin D receptor, estradiol is a ligand for the estrogen receptor α and β, chenodeoxycholic acid is a ligand for farnesoid X receptor, and rifampicin is a ligand for pregnane X receptor. MW, Molecular weight.

Fig. 5.

Schematic Illustration the Pathway Responsible for Biosynthesis of Heme, the Ligand for REV-ERBα and REV-ERBβ CoA, Coenzyme A.