The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.
Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbalpha 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-erbalpha mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbalpha 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-erbalpha 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-erbalpha.
Yin
Lei
L
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia 19104-6149, USA.
Lazar
Mitchell A
MA
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002940:Circadian Rhythm; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C539127:NCOR1 protein, human; C064353:NR1D1 protein, human; C539128:Ncor1 protein, mouse; C498262:Nr1d1 protein, mouse