SIRT1 regulates circadian clock gene expression through PER2 deacetylation

Cell. 2008 Jul 25;134(2):317-28. doi: 10.1016/j.cell.2008.06.050.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Trans-Activators
  • Transcription Factors
  • CLOCK Proteins
  • Clock protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins