Author:

Keywords:

Cell Line, Circular Dichroism, DNA-Binding Proteins, Gene Expression Regulation, Heme, Humans, Ligands, Nuclear Receptor Subfamily 1, Group D, Member 1, Receptors, Cytoplasmic and Nuclear, Recombinant Proteins, Repressor Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Spectrophotometry, Ultraviolet, Thermodynamics, Transcription Factors, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biophysics, Cell Biology, DELTA-AMINOLEVULINATE SYNTHASE, CIRCADIAN CLOCK, GENE-EXPRESSION, TRANSCRIPTIONAL REGULATION, MOLECULAR-CLONING, TARGET GENE, ROR-ALPHA, E-REGION, BINDING, MEMBER, 03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences, 34 Chemical sciences

Abstract:

The nuclear receptors REV-ERBalpha (encoded by NR1D1) and REV-ERBbeta (NR1D2) have remained orphans owing to the lack of identified physiological ligands. Here we show that heme is a physiological ligand of both receptors. Heme associates with the ligand-binding domains of the REV-ERB receptors with a 1:1 stoichiometry and enhances the thermal stability of the proteins. Results from experiments of heme depletion in mammalian cells indicate that heme binding to REV-ERB causes the recruitment of the co-repressor NCoR, leading to repression of target genes including BMAL1 (official symbol ARNTL), an essential component of the circadian oscillator. Heme extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids described so far. Our results further indicate that heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock.