The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control.
Circadian rhythms govern a large array of metabolic and physiological functions. The central clock protein CLOCK has HAT properties. It directs acetylation of histone H3 and of its dimerization partner BMAL1 at Lys537, an event essential for circadian function. We show that the HDAC activity of the NAD(+)-dependent SIRT1 enzyme is regulated in a circadian manner, correlating with rhythmic acetylation of BMAL1 and H3 Lys9/Lys14 at circadian promoters. SIRT1 associates with CLOCK and is recruited to the CLOCK:BMAL1 chromatin complex at circadian promoters. Genetic ablation of the Sirt1 gene or pharmacological inhibition of SIRT1 activity lead to disturbances in the circadian cycle and in the acetylation of H3 and BMAL1. Finally, using liver-specific SIRT1 mutant mice we show that SIRT1 contributes to circadian control in vivo. We propose that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock.
Nakahata
Yasukazu
Y
Department of Pharmacology, University of California, Irvine, CA 92697, USA.
Kaluzova
Milota
M
Grimaldi
Benedetto
B
Sahar
Saurabh
S
Hirayama
Jun
J
Chen
Danica
D
Guarente
Leonard P
LP
Sassone-Corsi
Paolo
P
D056930:ARNTL Transcription Factors; D000107:Acetylation; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D056926:CLOCK Proteins; D042002:Chromatin Assembly and Disassembly; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009243:NAD / Q000378:metabolism; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D008239:Lysine; D009243:NAD; D056564:Sirtuin 1; D037761:Sirtuins; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C498260:Dbp protein, mouse; C538944:Clock protein, mouse; C470545:Sirt1 protein, mouse