title: Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1.
abstract: Circadian rhythms govern a wide variety of physiological and metabolic functions in many organisms, from prokaryotes to humans. We previously reported that silent information regulator 1 (SIRT1), a NAD(+)-dependent deacetylase, contributes to circadian control. In addition, SIRT1 activity is regulated in a cyclic manner in virtue of the circadian oscillation of the coenzyme NAD(+). Here we used specific SIRT1 activator compounds both in vitro and in vivo. We tested a variety of compounds to show that the activation of SIRT1 alters CLOCK:BMAL1-driven transcription in different systems. Activation of SIRT1 induces repression of circadian gene expression and decreases H3 K9/K14 acetylation at corresponding promoters in a time-specific manner. Specific activation of SIRT1 was demonstrated in vivo using liver-specific SIRT1-deficient mice, where the effect of SIRT1 activator compounds was shown to be dependent on SIRT1. Our findings demonstrate that SIRT1 can fine-tune circadian rhythm and pave the way to the development of pharmacological strategies to address a broad range of therapeutic indications.
authors: Center for Epigenetics and Metabolism, Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
authors: Marina M
authors: MM
authors: Bellet
authors: Yasukazu
authors: Y
authors: Nakahata
authors: Mohamed
authors: M
authors: Boudjelal
authors: Emma
authors: E
authors: Watts
authors: Danuta E
authors: DE
authors: Mossakowska
authors: Kenneth A
authors: KA
authors: Edwards
authors: Marlene
authors: M
authors: Cervantes
authors: Giuseppe
authors: G
authors: Astarita
authors: Christine
authors: C
authors: Loh
authors: James L
authors: JL
authors: Ellis
authors: George P
authors: GP
authors: Vlasuk
authors: Paolo
authors: P
authors: Sassone-Corsi
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D020536:Enzyme Activators / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D056930:ARNTL Transcription Factors; D002843:Chromatin; D020536:Enzyme Activators; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D009243:NAD; D056926:CLOCK Proteins; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1