PMID:18662546

Citation	Asher, G, Gatfield, D, Stratmann, M, Reinke, H, Dibner, C, Kreppel, F, Mostoslavsky, R, Alt, FW and Schibler, U (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134:317-28
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.
Links	PubMed Online version:10.1016/j.cell.2008.06.050
Keywords	ARNTL Transcription Factors; Acetylation; Animals; Basic Helix-Loop-Helix Transcription Factors/metabolism; CLOCK Proteins; Cell Cycle Proteins/metabolism; Cells, Cultured; Circadian Rhythm; Embryo, Mammalian/cytology; Fibroblasts/metabolism; Gene Expression Regulation; Liver/metabolism; Mice; NIH 3T3 Cells; Nuclear Proteins/metabolism; Period Circadian Proteins; Sirtuin 1; Sirtuins/metabolism; Trans-Activators/metabolism; Transcription Factors/metabolism
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