Interplay Between the Circadian Clock and Sirtuins

Abstract

The circadian clock is an autonomous timekeeping system evolved by organisms to adapt to external changes, regulating a variety of important physiological and behavioral processes. Recent studies have shown that the sirtuin family of histone deacetylases is involved in regulating the expression of clock genes and plays an important role in maintaining the normal rhythm of clock gene expression and behavior. Moreover, sirtuins are regulated directly or indirectly by the circadian clock system. The mutual regulation between the circadian clock and sirtuins is likely involved in a variety of signal transduction and metabolism processes. In this review, we discuss the molecular mechanisms and research progress on the intertwined relationship between the circadian clock and sirtuins, mainly in mammals, highlighting sirtuins as molecular links between metabolic control and circadian rhythms and offering our perspectives on future developments in the field.

Keywords: circadian clock; circadian rhythm; clock gene; metabolism; sirtuin.

Figure 1

Molecular architecture of the core and interlocked feedback loops in mammals. At the core of these loops, BMAL1 and CLOCK form a heterodimeric transcriptional activator complex that binds to E-box motifs at promoters and enhancers to activate the transcription of the Per1, Per2, Per3, Cry1, and Cry2 genes. PER and CRY form heterodimers and suppress their own transcription by inhibiting CLOCK-BMAL1 transcriptional activity. The second feedback loop is composed primarily of Rev-erbα, which serves as a direct target of the CLOCK-BMAL1 transcriptional activator complex. REV-ERBα provides negative feedback by inhibiting the transcription of Bmal1 and competes with the retinoic acid-related orphan receptor (ROR) for binding to REV-ERB/ROR-binding elements (RREs) within the Bmal1 promoter. In the last loop, NFIL3 and DBP inhibit and activate the expression of D-box genes, respectively, to regulate the rhythm of ROR nuclear receptors. All loops also control the expression of clock-controlled genes (Ccgs), which mediate circadian output. Selected factors that mediate post-translational modifications and degradation of specific clock proteins are shown. The arrows depict the synthesis, assembly, and/or localization of clock proteins; the blocked line denotes repression; BMAL1 is also known as ARNTL; CK1, casein kinase 1; AMPK, AMP-activated protein kinase; P, phosphorylation; E, E-box; RRE, REV-ERB/ROR response element; Ub, ubiquitylation.

Figure 2

The mutual regulatory mechanisms between sirtuins and the circadian clock. NAD⁺ is a cellular energy sensor and sirtuins use NAD⁺ as a co-factor. The circadian clock regulates the activity of sirtuins through multiple mechanisms, including indirectly modulating sirtuin activity by controlling the rhythmic expression of Nampt to regulate NAD⁺ oscillation levels and directly influencing the transcription of the Sirt1 or SIRT1 protein. SIRT1, in turn, interacts with CLOCK-BMAL1 to affect circadian rhythm amplitude and gene expression by deacetylating PER2, BMAL1, and histone H3 at circadian gene promoters. In contrast to SIRT1, SIRT6 interacts with CLOCK-BMAL1 and governs their chromatin recruitment to circadian gene promoters. SIRT6 can also affect the circadian clock by deacetylating PER2, whereas SIRT7 contributes to circadian clock regulation by deacetylating CRY1. NAM, nicotinamide; NMN, nicotinamide mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NMNAT1-3, nicotinamide mononucleotide adenyltransferase; Ac, acetylation; dinusoidal lines represent rhythmic mRNAs; arrows depict the synthesis, assembly, and/or localization of clock proteins; the blocked line denotes repression.