SIRT1 regulates circadian clock gene expression through PER2 deacetylation.

Authors: Asher G; Gatfield D; Stratmann M; Reinke H; Dibner C; Kreppel F; Mostoslavsky R; Alt FW; Schibler U

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.

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
Journal: Cell
Volume: 134
Issue: 2
Pages: 317-28
Date: July 30, 2008
PMID: 18662546
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Citation:

Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317-28.


Lifespan Factors:
  • Sirt1 sirtuin 1 (silent mating type information regulation 2, homolog) 1 (S. cerevisiae)


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