REVIEW CIRCADIAN BIOLOGY

Sirtuins and the circadian clock: Bridging chromatin and metabolism Selma Masri and Paolo Sassone-Corsi*

The circadian clock is a light-entrained biological system that follows the 24-hour cycle of the day, which enables precisely timed systemic cues that govern sleep-wake, endocrine, and metabolic rhythms (1, 2). The circadian clock is controlled by the central pacemaker located within the suprachiasmatic nucleus (SCN), a region of the hypothalamus that receives input from the retina transmitted by the retinohypothalamic tract (3, 4). External light cues, zeitgebers, synchronize the central clock, which subsequently governs biological rhythms in all peripheral tissues through several secreted factors and possibly other undefined mechanisms (3, 5–8). The core clock machinery comprises the dimerizing transcription factors CLOCK and BMAL1, which drive transcription of the core clock genes and clock-controlled genes (CCGs). The expression of about 10% of the mammalian genome oscillates in a circadian manner, though the CCGs in any given tissue are vastly divergent (9, 10), indicating that extensive tissue specificity governs peripheral biological rhythms (11). For example, several tissue-specific transcription factors oscillate in a circadian manner (12), thereby controlling defined gene expression and metabolic programs in the liver, muscle, or adipose tissue. A number of factors contribute to the precisely timed control of the circadian clock. The protein products of the core clock genes Period (PER) (13, 14) and Cryptochrome (CRY) (15) provide negative feedback by repression of circadian transcription (16), although PER can inhibit CRYmediated transcriptional repression, suggesting that the role of PER proteins may be more complex (17). Additionally, the mammalian sirtuins (SIRTs), homologs of yeast silent information regulator 2 (Sir2), control the circadian clock at multiple levels. SIRTs compose the nicotinamide adenine dinucleotide (NAD+)–dependent class III family of histone deacetylases (HDACs), comprising seven members, which are implicated in various physiological functions including aging, maintenance of genome integrity, stress and nutrient challenge, metabolism, and cancer (18–20). Remarkably, SIRTs vary in enzymatic activity (deacetylase, adenosine diphosphate–ribosyl transferase, desuccinylase, demalonylase, demyristoylase, and depalmitoylase activities), biological targets, and cellular function (21, 22). The subcellular localization of SIRTs is also varied, thus dictating the diverse roles of these proteins. SIRT1 shuttles Center for Epigenetics and Metabolism, Department of Biological Chemistry, U904 INSERM, University of California, Irvine, Irvine, CA 92697, USA. *Corresponding author. Email: [email protected]

between the nucleus and the cytoplasm; SIRT2 is cytoplasmic; SIRT3, SIRT4, and SIRT5 are mitochondrial; SIRT6 is nuclear; and SIRT7 is found in the nucleolus (19, 23) (Fig. 1). This review highlights the known roles of SIRT1 in regulating the central (24) and peripheral (25, 26) circadian clock. Until recently, the question regarding the role of other mammalian SIRTs in the nucleus and mitochondria was unresolved. Recent evidence defines a role for SIRT3 in regulating circadian mitochondrial function and oxidative capacity (27). Given the key transcriptional output dictated by the circadian clock, we also describe recent evidence that characterizes SIRT6 in controlling the circadian clock at the chromatin level, defining a SIRT6-dependent circadian genomic landscape that is different from that of SIRT1 (28). We highlight the common control mechanism that dictates circadian SIRT activity and speculate on the ability of known endogenous activators, such as free fatty acids (FFAs), in defining functional specificity among SIRTs. Last, we discuss possible unexplored molecular connections between SIRT biology and the circadian clock in the context of the effects of dietary challenge on these processes. The Circadian Roles of SIRT1

SIRT1 regulates both the central and peripheral circadian clocks. Initial reports revealed that SIRT1 is critical in regulating the circadian genomic landscape in mouse liver (Fig. 2). SIRT1 deacetylates the circadian repressor PER2, promoting PER2 degradation and rhythmicity of the circadian cycle (25). SIRT1 also deacetylates BMAL1 and is recruited by the CLOCK and BMAL1 transcriptional complex to the promoters of CCGs, resulting in deacetylation of Lys9 and Lys14 of histone H3 and subsequent regulation of gene expression (26). SIRT1-mediated deacetylation of BMAL1 is important for the regulation of circadian transcription (29). The activity of SIRT1, but not the protein abundance of SIRT1, is circadian (26), suggesting that secondary factors are involved in regulating SIRT1 activity (see “Circadian regulation of SIRT activity” section). Thus, SIRT1 is a critical deacetylase in the regulation of expression of CCGs in the liver. Recent studies show that SIRT1 regulates the central clock in the SCN and is linked to aging [for reviews on SIRTs and aging, see (30, 31)]. Mice with brain-specific knockout of Sirt1 (BSKO) show marked dampening in circadian gene expression in the anterior hypothalamus, the region of the brain that contains the SCN, suggesting that SIRT1 positively regulates the

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The circadian clock is a finely tuned system of transcriptional and translational regulation that is required for daily synchrony of organismal physiological processes. Additional layers of complexity that contribute to efficient clock function involve posttranslational modifications and enzymatic feedback loops. SIRT1, the founding member of the sirtuin family of protein deacetylases, was the first sirtuin to be reported to modulate circadian function. SIRT1 affects the circadian clock by its actions in the nucleus. Moreover, recent data implicate SIRT3 and SIRT6 in controlling mitochondrial and nuclear circadian functions, revealing previously unappreciated roles that extend to various subcellular domains, including fatty acid metabolism in the mitochondria. This review focuses on the roles of sirtuins in directing circadian functions in diverse organelles and speculates on the endogenous signals that may mediate the segregated roles of this family of enzymes.

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expression of CCGs (24). BSKO mice have a lengthened circadian period and increased BMAL1 acetylation (a readout for SIRT1 activity) (24), suggesting that changes in gene expression mirror altered circadian function. In wild-type mice, the abundance of SIRT1, BMAL1, and PER2 proteins in the SCN declines with age (24). Moreover, young BSKO mice have dampened gene expression of Sirt1, Bmal1, and Per2, and resulting decreases in protein abundance, in the SCN compared to young wild-type mice (24), suggesting that loss of SIRT1 in the brain not only disrupts the circadian clock but also may alter the aging process. Thus far, SIRT1 is the only SIRT implicated in control of both the central and peripheral clocks. However, further investigation is needed to definitively address this point because other SIRTs, such as Sirt6, are highly expressed in the brain (32, 33). Moreover, the implication of SIRTs in aging may be connected to the circadian clock through changes in the abundance of the coenzyme NAD+, which declines with age in both mice and worms (34, 35). In the mouse hippocampus, decreased NAD+ correlates with decreased abundance of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+-salvage pathway (36). Further investigation is needed to determine whether the circadian clock controls the age-dependent decline in NAMPT and NAD+ and, subsequently, the circadian activity of SIRTs (see “Circadian regulation of SIRT activity” section). SIRT6 and Partitioning of the Circadian Genome

Redundancy among mammalian SIRTs, especially in the nucleus, implies that other SIRTs may regulate circadian transcription. Among the seven SIRTs, only SIRT1 and SIRT6 contain nuclear localization sequences, and only SIRT1 and SIRT2 contain nuclear export sequences (23, 37, 38). Because SIRT6 lacks a nuclear export sequence, the nuclear localization sequence of SIRT6 likely maintains its nuclear occupancy. SIRT6 localizes on chromatin (33, 38) and appears to remain bound to chromatin throughout the circadian cycle (28). The genome-wide occupancy of SIRT6 is enriched at binding sites for Ser5 phosphorylated RNA polymer-

Circadian Mitochondrial Functions and SIRT3

The circadian clock is intimately linked to mitochondrial biogenesis. In humans and mouse models, the abundance of multiple hepatic and serum metabolites shows circadian oscillation, indicating that mitochondrial processes could be linked to the circadian clock (49–51). Calorie restriction, which activates mitochondrial biogenesis (52), resets circadian gene expression and feeding rhythms in mice (53). Calorie restriction also increases the abundance and activity of mitochondrial SIRT3 and thereby regulates fatty acid oxidation (FAO), because loss of SIRT3 decreases the rate of FAO under fasting conditions (54, 55). SIRT1 (56, 57), SIRT6 (58), or SIRT3 (59) can activate or repress transcription of genes regulated by peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1a), a master regulator of mitochondrial biogenesis. Moreover, analysis of the acetylated proteome reveals that the liver contains circadian changes in lysine acetylation of a large number of mitochondrial proteins involved in amino acid metabolism, fatty acid elongation and metabolism, oxidative phosphorylation, citric acid cycle, and glycolysis and gluconeogenesis (60). Collectively, these findings indicate a major role of the interaction of the circadian clock and SIRTs in mitochondrial biogenesis in mammals.

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Fig. 1. The seven mammalian SIRTs. Protein structures and subcellular localizations of the seven mammalian SIRTs are illustrated. The core SIRT catalytic domain is indicated in white, with the flanking N- and C-terminal domains. The red boxes indicate locations of the nuclear localization sequences (NLS), whereas the blue boxes are the nuclear export sequences (NES).

ase II, a marker of the transcriptional start sites of active genomic loci (39). The chromatin binding of SIRT6 is dynamic in response to stimuli, such as tumor necrosis factor–a, thus creating the ability to provide an altered transcriptional landscape in response to aging or stress (40). SIRT6 deacetylates Lys9 (41, 42) and Lys56 of histone H3 (43–45), resulting in modulation of gene expression, telomere maintenance, and genomic stability (46, 47). Moreover, free histones are not deacetylated by SIRT6 in vitro, suggesting that the robust HDAC activity of SIRT6 is exclusively nucleosome-dependent (48). SIRT6 regulates circadian gene expression (Fig. 2). Microarray analysis of liver-specific Sirt6- and Sirt1-deficient mice at different times of day shows that SIRT6 regulates the expression of hepatic CCGs and that genes regulated by SIRT6 are largely exclusive from those regulated by SIRT1 (28). Moreover, SIRT6 is necessary for the recruitment of the circadian transcription factors to the promoters of target genes because loss of SIRT6 increases recruitment of BMAL1 and acetylation of Lys9 histone H3 at target CCG promoters (28). In addition to recruitment of the core clock machinery, SIRT6 also modulates the circadian recruitment of the transcription factor SREBP-1 (sterol regulatory element–binding protein), because loss of SIRT6 results in increased recruitment of SREBP-1 to its target gene promoters, such as Fasn (28). Unlike SIRT6, loss of SIRT1 does not affect circadian regulation of transcription factor recruitment (28). Moreover, most SIRT1-dependent and SIRT6-dependent genes peak in expression at different circadian phases. Thus, the nuclear functions of SIRT6 and SIRT1 are distinct; SIRT1 functions as an HDAC targeting histone H3 and nonhistone circadian proteins, whereas SIRT6 organizes circadian chromatin recruitment of transcriptional machinery. The question still remains as to how the nuclear SIRTs have evolved different roles and what signals may dictate these functions in regulating circadian transcription. SIRT6 may be a marker of actively transcribed genomic loci, and given that CCGs are rhythmically transcribed every 24 hours, the chromatin-dependent localization of SIRT6 seems compatible with a role in circadian transcriptional control. The shuttling of SIRT1 between the nucleus and the cytoplasm may underlie a different role for SIRT1 as a deacetylase of both histones and nonhistone proteins. Furthermore, the ability of the SIRTs to be activated by different metabolites could dictate divergent functions of these proteins (see “Circadian regulation of SIRT activity” section), although these possibilities need to be tested experimentally.

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Fig. 3. Activation of SIRTs by NAD+ and FFAs. The activity of SIRT1, SIRT6, and SIRT3 depends on the coenzyme NAD+. Circadian regulation of Nampt transcription by CLOCK, BMAL1, and SIRT1 governs the amount of NAD+. SIRT6 deacetylase activity is activated by FFAs in vitro. SIRT1 and SIRT6 target different subsets of genes and metabolites with circadian oscillation.

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mitochondrial functions linked to aging (34), although the link between these effects and the circadian clock remains elusive. Nevertheless, these data suggest that SIRT3 may not be the only SIRT implicated in circadian regulation of mitochondrial function.

SRE SREBP-1 target promoters

Fig. 2. The nuclear functions of SIRT1 and SIRT6 implicated in clock control. SIRT1 and SIRT6 are involved in different mechanisms that modulate circadian gene expression in the nucleus. SIRT1 targets and deacetylates BMAL1, PER2, and Lys9 and Lys14 of histone H3. SIRT6 also deacetylates Lys9 of histone H3 that is involved in the recruitment of the circadian transcriptional machinery (CLOCK and BMAL1) to E-box containing CCG promoters and SREBP-1 to SRE (sterol regulatory element)–containing promoters. Ac, acetylation.

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SIRT3 may be a critical link between mitochondrial function and the circadian clock (Fig. 3). Livers and embryonic fibroblasts of Bmal1 knockout mice have decreased rates of mitochondrial oxygen consumption due to decreased FAO and glucose oxidation (27). Consistent with these observations, embryonic fibroblasts from mice with knockout of Cry1 and Cry2 show the opposite trend (27). The abundance of the NAD+ is decreased in mitochondrial preparations from livers of Bmal1 knockout mice, which correlates with increased protein acetylation and inhibition of the activity of the SIRT3 targets medium- and longchain acyl–coenzyme A (CoA) dehydrogenases (MCAD and LCAD) and isocitrate dehydrogenase 2 (IDH2) (27). Acetylation of IDH2 is also clockdependent and presumably regulates its circadian activity (60). Supplementation of Bmal1 knockout mice with nicotinamide mononucleotide (NMN) restores mitochondrial NAD+ and presumably SIRT3 activity in addition to the rates of oxygen consumption and FAO (27). Thus, these findings suggest cooperation between SIRT3 and the circadian machinery in the regulation of lysine acetylation and the activity of mitochondrial enzymes. However, given that all mammalian SIRTs are NAD+-dependent, the other mitochondrial SIRTs, SIRT4 and SIRT5, may also participate in clock-dependent regulation of oxidative pathways (Fig. 1). Moreover, NMN supplementation in mice has additional effects on SIRT1-mediated

Circadian Regulation of SIRT Activity

Circadian oscillation in the abundance of NAD+ (61, 62) controls the activity of the SIRTs in a clock-dependent manner. The circadian clock controls the expression of Nampt (Fig. 3). CLOCK, BMAL1, and SIRT1 bind consensus E-box motifs in the Nampt promoter in a circadian manner. Genetically impairing circadian clock function in mice abolishes the oscillatory expression of Nampt and, consequently, the cycling of NAD+ and SIRT1 activity in cultured embryonic fibroblasts and liver (61, 62). Similarly, pharmacological inhibition of NAMPT depletes NAD+ and impairs SIRT1 activity in mouse embryonic fibroblasts, leading to hyperacetylation of BMAL1 and disruption of circadian gene expression (61). Conversely, mice deficient for the NAD+ hydrolase CD38 have chronically elevated abundance of NAD+ and abnormal circadian behavior and metabolism (63). Thus, SIRT1-dependent regulation of the circadian clock establishes a transcriptional, translational, and enzymatic feedback loop to fine-tune its deacetylase activity by modulating the abundance of cellular NAD+. Although NAD+ is the primary coenzyme for the SIRTs, recent data indicate that other metabolites modulate SIRT activity. FFAs (myristic, oleic, or linoleic acid) induce a 35-fold increase in SIRT6 catalytic activity but do not affect the activity of SIRT1 (64). Because the structures of these FFAs are diverse, including both saturated and unsaturated FFAs, this study implies that SIRT6 may not have specificity for a particular aliphatic tail. Moreover, endogenous FFAs may play a role in activating or sensitizing SIRT6 in vivo, which would provide functional specificity over other SIRTs, although this remains untested. Loss of hepatic SIRT6 in mice disrupts circadian oscillation in the metabolism of fatty acids, including mediumand long-chain fatty acids, triglycerides, membrane lipids, and signaling lipids (28). Thus, similar to the regulation of NAD+ by SIRT1, SIRT6mediated regulation of fatty acid metabolism may represent a feedback

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REVIEW mechanism for FFA-mediated modulation of SIRT6 activity in vivo. In addition, further complexity arises from the observation that SIRT1 modulates the activity of acetyl-CoA synthetase 1, resulting in circadian oscillation of acetyl-CoA that contributes to fatty acid elongation (65). Thus, multiple SIRTs differentially control various steps of fatty acid homeostasis, and further investigation of the physiological relevance of these findings may reveal a contribution of SIRT1 or SIRT3 to the activation of SIRT6 by FFAs. Therapeutic Modulation of SIRT Activity

Concluding Remarks

Here, we discussed the roles of SIRT1, SIRT3, and SIRT6 in modulating the circadian gene expression, epigenetics, and metabolism. An obvious question is whether other SIRTs could also be involved in circadian functions. Given that NAD+ oscillates in a circadian manner, all SIRTs may have rhythmic activity profiles. The subcellular localization of other SIRTs suggests that they may have distinct cellular functions. For example, SIRT2 resides in the cytoplasm, which could implicate a different population of protein targets, potentially also regulated in a circadian manner. SIRT7 localizes to the nucleolus and evidence implicates the circadian clock in the regulation of ribosome biogenesis (81), suggesting an additional cellular compartment that may be affected by circadian SIRT activity. Thus, as more information emerges regarding the role of the SIRTs in regulating clock function, new areas of research could provide exciting avenues for intervention in diseases related to metabolism, aging, and cancer. REFERENCES 1. S. Sahar, P. Sassone-Corsi, Regulation of metabolism: The circadian clock dictates the time. Trends Endocrinol. Metab. 23, 1–8 (2012). 2. J. Bass, Circadian topology of metabolism. Nature 491, 348–356 (2012). 3. U. Schibler, P. Sassone-Corsi, A web of circadian pacemakers. Cell 111, 919–922 (2002). 4. D. K. Welsh, J. S. Takahashi, S. A. Kay, Suprachiasmatic nucleus: Cell autonomy and network properties. Annu. Rev. Physiol. 72, 551–577 (2010). 5. S. J. Aton, C. S. Colwell, A. J. Harmar, J. Waschek, E. D. Herzog, Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8, 476–483 (2005). 6. S. Masri, P. Sassone-Corsi, The circadian clock: A framework linking metabolism, epigenetics and neuronal function. Nat. Rev. Neurosci. 14, 69–75 (2013). 7. M. Y. Cheng, C. M. Bullock, C. Li, A. G. Lee, J. C. Bermak, J. Belluzzi, D. R. Weaver, F. M. Leslie, Q. Y. Zhou, Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002). 8. A. Kramer, F. C. Yang, P. Snodgrass, X. Li, T. E. Scammell, F. C. Davis, C. J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001). 9. R. A. Akhtar, A. B. Reddy, E. S. Maywood, J. D. Clayton, V. M. King, A. G. Smith, T. W. Gant, M. H. Hastings, C. P. Kyriacou, Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2002). 10. S. Panda, M. P. Antoch, B. H. Miller, A. I. Su, A. B. Schook, M. Straume, P. G. Schultz, S. A. Kay, J. S. Takahashi, J. B. Hogenesch, Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002). 11. S. Masri, P. Sassone-Corsi, Plasticity and specificity of the circadian epigenome. Nat. Neurosci. 13, 1324–1329 (2010). 12. X. Yang, M. Downes, R. T. Yu, A. L. Bookout, W. He, M. Straume, D. J. Mangelsdorf, R. M. Evans, Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006). 13. U. Albrecht, Z. S. Sun, G. Eichele, C. C. Lee, A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell 91, 1055–1064 (1997). 14. L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski Jr., S. M. Reppert, Two period homologs: Circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19, 1261–1269 (1997). 15. R. J. Thresher, M. H. Vitaterna, Y. Miyamoto, A. Kazantsev, D. S. Hsu, C. Petit, C. P. Selby, L. Dawut, O. Smithies, J. S. Takahashi, A. Sancar, Role of mouse cryptochrome bluelight photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998). 16. K. Padmanabhan, M. S. Robles, T. Westerling, C. J. Weitz, Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science 337, 599–602 (2012). 17. M. Akashi, A. Okamoto, Y. Tsuchiya, T. Todo, E. Nishida, K. Node, A positive role for PERIOD in mammalian circadian gene expression. Cell Rep. 7, 1056–1064 (2014).

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Given the role of the SIRTs in circadian rhythms, metabolism, aging, and cancer, it is imperative to modulate the activity of these HDACs in vivo. SIRT-activating compounds (STACs), which specifically target SIRT1, are beneficial for treating type 2 diabetes and metabolic disorders as a result of diet-induced obesity in mice (66, 67). In addition, STACs modulate circadian rhythms by targeting SIRT1-dependent regulation of the CLOCK and BMAL1 transcription complex and the expression of CCGs in vitro and in vivo (68). Thus, targeting SIRTs for therapeutic purposes may be possible. The diverse functions and differences in subcellular distribution of the mammalian SIRTs will be important to consider for pharmacological intervention. Except for SIRT1, which shuttles between the nucleus and the cytoplasm, SIRTs maintain strict subcellular localization (Fig. 1). Therefore, it follows that SIRTs should perform highly specialized functions within the cell. Indeed, SIRT1 and SIRT6 play unique, partitioned roles in regulating the nuclear functions of the circadian clock (24–26, 28). Another example related to the role of the SIRTs in the mitochondria is not as well understood. Supplementation with nicotinamide riboside, a NAD+ precursor, activates SIRT1 and thereby improves the function of the mitochondrial respiratory chain in a mouse model of mitochondrial disease caused by loss of cytochrome c oxidase (69). Thus, why does SIRT1, which does not localize in mitochondria, play a role in regulating mitochondrial function, and can other mitochondrial SIRTs, such as SIRT3, SIRT4, or SIRT5, substitute for SIRT1? In addition, the specific enzymatic activities of SIRTs may be affected differently by different drugs. For example, SIRT3 has intrinsic deacetylase activity, whereas SIRT5 does not have strong deacetylase activity but robustly desuccinylates carbamoyl phosphate synthase 1, the rate-limiting enzyme of the urea cycle (70). How does the interplay of target specificity, subcellular localization, and the specific enzyme activities of different SIRTs determine cellular responses, including the regulation of circadian rhythms? These and related issues are critical to consider in efforts to identify and characterize therapeutically relevant pharmacological activators and inhibitors of SIRTs. Dietary intake is also relevant to consider regarding SIRT activity and influence on the circadian clock. Overall calorie restriction or time-restricted feeding paradigms can alter the expression or activity of SIRT1 (71, 72), SIRT3 (54, 55), and SIRT6 (73). In addition, transgenic overexpression of SIRT1 (74, 75), SIRT6 (76), or SIRT3 (77) protects against, whereas ablation of these SIRTs accelerates, metabolic defects caused by high-fat diet in mice. Calorie restriction alters the expression of CCGs and circadian feeding behavior in mice (53), and high-fat diet induces changes in the length of the circadian period, the expression of CCGs, and the circadian metabolome (78–80). There may be a direct connection between the dietinduced changes in circadian timekeeping and changes in SIRT activity. Feeding mice a high-fat diet abolishes the circadian oscillation of NAD+ abundance (78), which strongly suggests secondary effects on circadian SIRT activity. However, other endogenous activators may also play a role in diet-induced changes in circadian SIRT activity. In mice fed a high-fat diet, the amounts of linoleic and oleic acids are chronically elevated across

the circadian cycle (78), suggesting that, at least with respect to modulation of SIRT6 by diet, the loss of NAD+ oscillation could be counteracted by changes in endogenous fatty acids. Thus, the effects of different diets on the SIRTs and whether these might be beneficial in treating disease deserve further investigation.

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Submitted 14 July 2014 Accepted 20 July 2014 Final Publication 9 September 2014 10.1126/scisignal.2005685 Citation: S. Masri, P. Sassone-Corsi, Sirtuins and the circadian clock: Bridging chromatin and metabolism. Sci. Signal. 7, re6 (2014).

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Sirtuins and the circadian clock: Bridging chromatin and metabolism Selma Masri and Paolo Sassone-Corsi (September 9, 2014) Science Signaling 7 (342), re6. [doi: 10.1126/scisignal.2005685]

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