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Fig. 1. Circadian Bmal1 expression is regulated by competitive binding of REV-ERBs and RORs to RRE in the Bmal1 promoter. RRE, the cis-element recognized by the circadian nuclear receptor REV-ERBα, overlaps with NBRE, which is recognized by the nuclear receptor NURR1 in the TH promoter. REV-ERBα antagonizes NURR1-induced activation of the TH promoter via binding to RRE/NBRE, thereby contributing to the circadian rhythmicity of the DAergic system. REV-ERBα controls circadian TH gene transcription by recruiting the corepressors N-CoR and HDAC3, which suppress TH gene transcription by negatively modifying permissive histone acetylation. SN, substantia nigra; VTA, ventral tegmental area; NAc, nucleus accumbens; DA, dopamine; TH, tyrosine hydroxylase; RORs, retinoic acid receptor-related to orphan nuclear receptors; RRE, ROR/REV-ERB response element; NBRE, NGFI-B response element; N-CoR, nuclear receptor co-repressor 1; HDAC3, histone deacetylase 3; NURR1, nuclear receptor related 1 protein.
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