Figure 4.

The regulation of central and peripheral clock genes by SIRT1. When dimerized, the core clock genes CLOCK and BMAL1 promote the expression of several downstream genes including their own negative regulators periods (PER) and cryptochromes (CRY). PER and CRY accumulate during the day and together with casein kinase 1 (CK1) then repress their own transcription. The CLOCK-BMAL1 complex also regulates the retinoic acid-related orphan receptors (ROR) and the nuclear receptors (Rev-Erb), which compete for the regulation of the BMAL1 promoter. In the peripheral clocks, SIRT1 regulates the circadian genes at different levels. SIRT1 protein levels cycle in a circadian manner, and through its rhythmic binding to the CLOCK-BMAL1 complex SIRT1 promotes the circadian transcription of Bmal1, Rorγ, Per2, and Cry1. SIRT1 also promotes the deacetylation and degradation of the PER2 protein. SIRT1 activity has also been reported to cycle in a circadian manner owing to the rhythmic expression of NAMPT, a crucial enzyme for NAD⁺ biosynthesis, by the CLOCK-BMAL1 complex. In turn, SIRT1 also acts as a negative regulator of the CLOCK-BMAL1 complex thus preventing the activation of circadian promoters. In the suprachiasmatic nucleus (SCN), SIRT1 activates the transcription of the circadian genes BMAL1 and CLOCK through PGC-1α.