SIRT1 regulates circadian clock gene expression through PER2 deacetylation

Area of Science:

• Chronobiology
• Molecular Biology
• Biochemistry

Background:

• The mammalian circadian timing system relies on a molecular feedback loop involving transcription factors like BMAL1 and CLOCK.
• Period (Per) and Cryptochrome (Cry) genes are activated by BMAL1-CLOCK, with their proteins forming complexes to repress their own transcription.

Purpose of the Study:

• To investigate the role of SIRT1, an NAD(+)-dependent protein deacetylase, in the regulation of core circadian clock genes.
• To elucidate the mechanism by which SIRT1 influences circadian transcription and protein stability.

Main Methods:

• Investigated SIRT1's requirement for circadian transcription of core clock genes (Bmal1, Rorgamma, Per2, Cry1).
• Examined SIRT1's binding to CLOCK-BMAL1 heterodimers in a circadian manner.
• Assessed SIRT1's effect on PER2 deacetylation and degradation.

Main Results:

• SIRT1 is essential for high-magnitude circadian transcription of key clock genes, including Bmal1, Rorgamma, Per2, and Cry1.
• SIRT1 interacts with CLOCK-BMAL1 in a time-dependent manner.
• SIRT1 promotes the deacetylation and subsequent degradation of PER2 protein.

Conclusions:

• SIRT1 plays a critical role in regulating the amplitude of circadian gene expression.
• SIRT1 directly impacts the stability of PER2 protein within the core clock mechanism.
• SIRT1's NAD(+)-dependent activity suggests a direct link between cellular metabolism and the central circadian clockwork.