Nuclear receptors transduce environmental and metabolic signals into alterations in gene expression by recruiting coregulators that alter chromatin structure. The nuclear receptor PPARg is the target of antidiabetic thiazolidinedione (TZD) drugs, and a transcriptional regulator of lipid metabolism. The induction of PPARg is required for adipogenesis, and this is regulated by a coordination of hormonal, epigenomic, and transcriptional factors that define a novel early stage of adipognesis. In mature adipocytes, genomic binding of PPARg coordinates metabolic gene pathways that are conserved between rodents and humans. Rev-erbá is a nuclear heme receptor that functions as a component of a negative limb of the circadian clock. Heme binding to Rev-erbá stabilizes recruitment of a complex containing the corepressor NCoR and histone deacetylase 3 (HDAC3). In liver, circadian expression of Rev-erbá leads to its oscillating interaction with the genome, at a cistrome that is enriched near genes involved in lipid metabolism. This directs a circadian recruitment of NCoR and HDAC3 with a rhythm that is anti-phase to histone acetylation and recruitment of RNA polymerase II at these sites and at nearby genes.
The hepatic rhythm of histone acetylation is abrogated by depletion of HDAC3, which also induces many of the lipid metabolic genes bound by Rev-erbá and HDAC3 and causes massive triglyceride accumulation in the liver. Thus HDAC3 orchestrates a circadian epigenomic rhythm that is a major regulator of hepatic lipid metabolism. Comparative analysis of HDAC3 cistromes in other tissues reveals intriguing similarities and differences in transcription factor recruitment, gene targets, and circadian rhythms that may reflect their specific environments and functions. The epigenomic regulation and functions of Rev-erba and PPARg thus highlight the key role of nuclear receptors in the integrated physiology of circadian rhythm and metabolism.
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