Title:
Circadian Rhythm Regulation byNAD⁺-dependent protein deacetylase“SIRT1”

Yasukazu NAKAHATA, Ph.D
Assistant professor
Graduate School of Biological Sciences
Nara Institute of Science and Technology

Abstract:
Many metabolic and physiological processes display circadian oscillations and a series of studies using circadian gene deficient mice have demonstrated that circadian clock machinery is associated with many metabolisms and diseases. Although histone H3 acetylation status at circadian gene promoter has known to oscillate with 24-hour rhythm, this molecular mechanism remains to be elucidated. In this meeting, we show that the deacetylationactivity of the NAD⁺ -dependent protein deacetylaseSIRT1 is regulated in a circadian manner, correlating with rhythmic acetylation ofhistone H3 Lys9/Lys14 at circadian promoters.We also demonstrate that intracellular NAD⁺ levels cycle with a 24-hour rhythm, an oscillation driven by the circadian clock. SIRT1 physically interacts with circadian transcriptional activators, CLOCK/BMAL1, and they control the circadian expression of NAMPT (nicotinamidephosphoribosyltransferase), an enzyme that provides a rate-limiting step in the NAD⁺ salvage pathway.Our findings reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms.Finallywe propose that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock.

References:
Bellet MM,  Nakahata Y , Boudjelal M, Watts E, Mossakowska DE, Edwards KA, Cervantes M, Astarita G, Loh C, Ellis JL, Vlasuk GP,  Sassone-Corsi P . Pharmacological modulation ofcircadian rhythms by synthetic activators of the deacetylase SIRT1. ProcNatlAcadSci U S A . 2013 Jan 22.   [Epub ahead of print]

Nakahata Y , Sahar S, Astarita G, Kaluzova M,  Sassone-Corsi P . Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science . 2009 May 1;324(5927):654-7.

Nakahata Y , Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP,  Sassone-Corsi P . The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell . 2008 Jul 25;134(2):329-40.