SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation

Abstract

The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus of the brain that synchronizes countless subsidiary oscillators in peripheral tissues. The rhythm-generating mechanism is thought to rely on a feedback loop involving positively and negatively acting transcription factors. BMAL1 and CLOCK activate the expression of Period (Per) and Cryptochrome (Cry) genes, and once PER and CRY proteins accumulate to a critical level they form complexes with BMAL1-CLOCK heterodimers and thereby repress the transcription of their own genes. Here, we show that SIRT1, an NAD(+)-dependent protein deacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Rorgamma, Per2, and Cry1. SIRT1 binds CLOCK-BMAL1 in a circadian manner and promotes the deacetylation and degradation of PER2. Given the NAD(+) dependence of SIRT1 deacetylase activity, it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry.

The role of clock genes and rhythmicity in the liver

“…Interestingly, the nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylase SIRT1 was shown to be a regulator in the circadian clock mechanism ( Fig. 2; Asher et al, 2008;Nakahata et al, 2008). Furthermore, cellular NAD + levels cycle with a period of 24 h (Nakahata et al, 2009;Ramsey et al, 2009).…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Il a été mis en évidence que la concentration intracellulaire en nicotinamide adénine dinucléotide (NAD + ) synthétisé par la nicotinamide phosphoribosyltransférase (NAMPT) se trouve sous le contrôle de l'horloge et oscille de manière circadienne. En retour, le NAD + module l'activité de l'horloge via l'action de la désacétylase Sirt1, une enzyme activée par la restriction calorique et dont il est le cofacteur [24][25][26]. En désacétylant BMAL1, Sirt1 diminue son interaction avec l'ADN, tandis que CLOCK exerce une action opposée en acétylant BMAL1.…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…Other modifications include the ubiquitination of CRYs by F-box type ubiquitin ligases that targets them for M a n u s c r i p t degradation by the proteasome [25][26][27]. Furthermore, acetylation of BMAL1 and PER2 has been reported [28,29].…”

“…The histone deacetylase SIRT1 deacetylates not only histones, but also the core clock components BMAL1 and PER2 (most likely previously acetylated by CLOCK itself, which has HAT activity [28]), and it requires NAD+ as a cofactor [29,[51][52][53]. NAD+ levels show circadian oscillation, partially mediated by clock control of the rate limiting enzyme in NAD+ biosynthesis, nicotinamide phosphoribosyltransferase.…”