Another important question relates to whether SIRT1 would operate on other nonhistone circadian targets. CLOCK was found to interact with some nuclear receptors, including RARa and RXRa (McNamara et al., 2001). Since periodic availability of nuclear hormones has been implicated in the resetting of peripheral clocks (McNamara et al., 2001; Yin et al., 2007), and since SIRT1 has been found to control a number of nuclear receptors (see for example Li et al., 2007b), it is reasonable to speculate that the CLOCK-SIRT1 interaction described in this study represents a key event in the processes of fat and energy metabolism. In this respect, it is worth noting that PGC-1, a transcriptional coactivator that regulates energy metabolism and that acts in combination with SIRT1 (Nemoto et al., 2005; Rodgers et al., 2005), is rhythmically expressed in the liver and skeletal muscle and is required for cell-autonomous clock function (Liu et al., 2007; Sonoda et al., 2007). Thus, the CLOCK-SIRT1 interplay seems to occupy a privileged position in the control of gene expression by metabolites.
CLOCK and SIRT1 appear to be associated at all times of the circadian cycle (Figure 5), suggesting that they would not only coordinately contribute to the dynamic oscillation of histone acetylation but also regulate a number of nonhistonic targets.
The identification of additional molecular elements within the CLOCK:BMAL1/SIRT1 complex will define its functional features, leading to the unraveling of intracellular regulatory pathways yet poorly understood. In this respect, a fascinating connection is apparent between circadian metabolism, aging, and cancer. DNA damage accumulates with age and defects in DNA repair may lead to phenotypes reminiscent of premature aging (Lombard et al., 2005; Saunders and Verdin, 2007). The conceptual and functional link existing between the circadian clock and the cell cycle (Hunt and Sassone-Corsi, 2007; Chen and McKnight, 2007) has been extended to implicate the circadian machinery in the DNA-damage response (Collis and Boulton, 2007). The circadian genes per1 and tim have been shown to play an important role in DNA-damage control (Gery et al., 2006; Unsal-Kaçmaz et al., 2005), and phase resetting of the mammalian circadian clock is readily obtained by DNA-damaging agents (Oklejewicz et al., 2008). Finally, the role of SIRT1 in the aging process (Oberdoerffer and Sinclair, 2007; Bishop and Guarente, 2007) is intriguingly paralleled by recent observations of early aging and age-related pathologies observed in BMAL1-deficient mice (Kondratov et al., 2006). The far-reaching implications of our findings are thereby multiple, including the identification of novel strategies for the study of diabetes, obesity, and aging.
Experimental Procedures
Animals
Male BALB/c mice and liver-specific Sirt1−/− mice were housed under 12 hr light/12 hr dark (LD) cycles over 2 weeks. All protocols using animals were approved by the Institutional Animal Care and Use Committee of the University of California, Irvine.
Plasmids
FLAG-tagged and Myc-tagged plasmids have been described (Doi et al., 2006; Travnickova-Bendova et al., 2002). Full and truncated mouse Clock ORFs were amplified by PCR and cloned in pG4MpolyII vector. Mouse Clock(D19) was amplified by PCR from c/c MEFs. Mouse SIRT1 ORF was sub-cloned into pcDNA3 with a FLAG epitope sequence at the 5′ end. hSIRT1-Flag/pcDNA3.1, hSIRT2-Flag /pcDNA3.1, and hSIRT3-Flag /pcDNA3.1 were kind gifts of E. Verdin. Flag-hSIRT1/pECE, Flag-hSIRT1(H363Y)/pECE, hSIRT1-HA/pECE, and hSIRT1(H363Y)-HA/pECE were kind gifts of A. Brunet.
Antibodies
Antibodies against acetyl-histone H3, histone H4, and SIRT1 were from Millipore, antibodies against CLOCK and rabbit IgG from Santa Cruz Biotechnology, and antibodies against Flag (M2) and b-actin from Sigma. Antibodies against BMAL1 and Myc were described (Cardone et al., 2005). Polyclonal acetyl-lysine 537 BMAL1antibody was generated by immunizing rabbits with KLH-conjugates of the peptide NH2-ASSPGG[acetyl-K]KILN-(mouse BMAL1).
Cell Culture
MEFs were generated from WT or homozygous Sirt1−/− sibling mice and cultured in DMEM (4.5 g/l glucose) supplemented with 7.5% newborn bovine serum, 2.5% FBS, and antibiotics. JEG3 cells were grown in Basal Medium Eagle supplemented with 10% FBS and antibiotics.
Preparation of Cell Extracts and Nuclear Extracts from Cultured Cell Lines
Cells were washed twice with phosphate-buffered saline (PBS) and lysed in RIPA buffer (50 mM Tris/HCL [pH 8.0], 150 mM NaCl, 5 mM EDTA, 15 mM MgCl2, 1% NP40, 13 protease inhibitor cocktail [Roche], 1 mM DTT, 1 mM trichostatin A [TSA], 10 mM NAM, 10 mM NaF, 1 mM PMSF). For nuclear extracts (Andrews and Faller, 1991), after washing cells with cold PBS, cells were lysed with hypotonic buffer (10 mM HEPES-KOH [pH 7.9], 1.5 mM MgCl2, 10 mM KCl, 13 protease inhibitor cocktail [Roche], 1 mM DTT, 1 mM TSA, 10 mM NAM, 10 mM NaF, 1 mM PMSF). Following a brief centrifugation, pellet was resuspended in hypertonic buffer (20 mM HEPES-KOH [pH 7.9], 25% glycerol, 420 mM NaCl 1.5 mM MgCl2, 0.2 mM EDTA, 13 protease inhibitor cocktail [Roche], 1 mM DTT, 1 mM TSA, 10 mM NAM, 10 mM NaF, 1 mM PMSF). Supernatants were recovered as nuclear extracts.
ChIP Assays
Conventional ChIP assay was used for histones from MEFs (Yamamoto et al., 2004). For nonhistone proteins, dual crosslinking ChIP assay (Nowak et al., 2005) was used with slight modifications. After serum shock, cells were washed three times with room temperature PBS, then PBS/1 mM MgCl2 was added. Disuccinimidyl Glutalate (DSG) was added to a final concentration of 2 mM for crosslinking. After 45 min at room temperature, formaldehyde was added to a final concentration of 1%(v/v) and cells incubated for 15 min. After dual crosslinking, glycine was added to a final concentration of 0.1 M and incubated for 10 min to quench formaldehyde out. After harvesting, cells were lysed in 500 ml ice-cold cell lysis buffer (50 mM Tris/HCl [pH 8.0], 85 mM KCl, 0.5% NP40, 1 mM PMSF, 13 protease inhibitor cocktail [Roche]) for 10 min on ice. Nuclei were precipitated by centrifugation (3000 g for 5 min), resuspended in 600 ml ice-cold RIPA buffer (50 mM Tris/HCl [pH 8.0], 150 mM NaCl, 1 mM EDTA [pH 8.0], 1% Triton X-100, 0.1% SDS, 0.1% sodium deoxycholate, 1 mM PMSF, 13 protease inhibitor cocktail [Roche]), and incubated on ice for 30 min. Sonication was done to obtain DNA fragments 100–600 bp in length.
Quantitative Real-Time RT-PCR
Each quantitative real-time RT-PCR was performed using the Chromo4 real time detection system (BIO-RAD). The PCR primers for mDbp mRNA, mPer2 mRNA, mCry1 mRNA, 18S rRNA, Dbp UP, Dbp E-box, Dbp 3′R, and mSIRT1 mRNA were described (Ripperger and Schibler, 2006; Rodgers et al., 2005; Yamamoto et al., 2004). PCR primers for Dbp TSS were designed using Real-Time PCR Primer Design (
https://www.genscript.com/ssl-bin/app/primer), and the sequences are available upon request. For a 20 ml PCR, 50 ng of cDNA template was mixed with the primers to final concentrations of 200 nM and 10 ml of iQ SYBR Green Supermix (BIO-RAD), respectively. The reaction was first incubated at 95°C for 3 min, followed by 40 cycles at 95°C for 30 s and 60°C for 1 min.
RNase Protection Assays
RNA extractions were done using TRIzol (GIBCO BRL). RNase protection assays (RPAs) were performed as described (Pando et al., 2002). The riboprobes were generated using an in vitro transcription kit (Promega). Data were quantified using a phosphorimager.
Recombinant Proteins, [35S] Labeling, and GST Pulldown Assay
GST-fused recombinant proteins were expressed in E. coli BL21. Recombinant proteins were lysed by CelLytic B Cell Lysis Reagent (Sigma) according to the manufacturer’s protocol and purified by glutathione Sepharose 4B (Amersham). 35S-methionine-labeled proteins were made in vitro using the TNT-T7 quick-coupled transcription-translation system (Promega). Twenty microliters of in vitro-translated 35S-methionine-labeled proteins and 1 mg of GST-mSIRT1 or GST on glutathione Sepharose were added in a 1 ml binding buffer (50 mM Tris/HCl [pH 8.0], 150 mM NaCl, 1% NP-40), incubated over-night at 4°C. After washing sepharose with binding buffer three times, proteins were analyzed on SDS-PAGE.
SIRT1 Deacetylation Assay
SIRT1 deacetylase activity was determined using a SIRT1 Fluorimetric Activity Assay/Drug Discovery Kit (AK-555; BIOMOL International) following the manufacturer’s protocol. Extracts from serum-stimulated MEFs and liver from entrained mice lysed by RIPA buffer were used for measuring SIRT1 deacetylase activity. Complementation assays were performed by adding recombinant E. coli-generated SIRT1, and they included 1 U/reaction of SIRT1 protein and 25 mM of substrate (acetylated p53) in a 50 ml final volume. Endogenous SIRT1 from liver was obtained by immunoprecipitation and then incubated in deacetylase buffer with the substrate and 0.1 mM NAD+ for 1 hr at 37°C.
Acknowledgements
We thank F. Alt, A. Brunet, S. Masubuchi, D. Gauthier, S. Katada, S.B. Curto, E. Verdin, S. Dilag, and all members of the Sassone-Corsi laboratory for help, reagents, and discussions. This work was supported by grants of the Cancer Research Coordinating Committee of the University of California and of the NIH (R01-GM081634-01) to P. S.-C.
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