The Orphan Nuclear Receptor Rev-erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene

L Yin, MA Lazar - Molecular endocrinology, 2005 - academic.oup.com
Molecular endocrinology, 2005academic.oup.com
Transcriptional regulation plays a fundamental role in controlling circadian oscillation of
clock gene expression. The orphan nuclear receptor Rev-erbα has recently been implicated
as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of
circadian rhythm in mammals, is negatively correlated with Rev-erbα mRNA level, but the
molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-
erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two …
Abstract
Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbα has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbα mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbα directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbα.
Oxford University Press