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Journal ArticleDOI

The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control

TL;DR: It is proposed that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock.
About: This article is published in Cell.The article was published on 2008-07-25 and is currently open access. It has received 1261 citations till now. The article focuses on the topics: Circadian clock & CLOCK.
Citations
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Journal ArticleDOI
TL;DR: This work discusses knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system and some of the SCN output pathways serve as input pathways for peripheral tissues.
Abstract: Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

1,984 citations


Cites background from "The NAD+-Dependent Deacetylase SIRT..."

  • ...Mammalian SIRT1, an NAD+-dependent deacetylase, has been recently identified as a novel regulator of circadian gene expression (242, 243)....

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Journal ArticleDOI
TL;DR: There have been major advances in the understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span, and the challenges that will confront the field in the coming years are discussed.
Abstract: Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.

1,765 citations


Cites background from "The NAD+-Dependent Deacetylase SIRT..."

  • ...For example, is SIRT1 induced in liver by fasting or by CR? Are earlier studies on SIRT1 now more difficult to interpret given that we know SIRT1 and its regulator, Nampt, are key components of the circadian clock that vary over a 12-h cycle (51, 53, 291, 292)? NAD+ is an important physiological regulator of sirtuins, even in mitochondria (44), yet it is still not clear how NAD+ is synthesized in various cellular compartments....

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Journal ArticleDOI
TL;DR: An emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.
Abstract: The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

1,674 citations


Cites background from "The NAD+-Dependent Deacetylase SIRT..."

  • ...The ratio of NAD+ to NADH influences binding of NPAS2:BMAL1 and CLOCK:BMAL1 to DNA in vitro, suggesting one way in which NAD could interact with clock components (Rutter et al. 2001)....

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  • ...F or p er so na l u se o nl y. REV-ERBsRRE Bmal1 RORs REV-ERBs CRYs PERs BMAL1 CLOCK BMAL1 CLOCK E-box Rev-erbα RORs E-box Rorα E-box Cry1/Cry2 E-box Per1/Per2 PER CRY CK1ε/δ PER CRY CK1ε/δ E-box Ccg Clock outputs/ rhythmic biological processes CK1 β-TrCP SCF Proteosome Nuclear translocation Repression +Ub 26S SCF FBXL3 AMPK +Ub 26S C Y T O P L A S M N U C L E U S Figure 1 The molecular mechanism of the circadian clock in mammals....

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  • ...HNF4α is responsive to glucocorticoids (Reddy et al. 2007), contains E-boxes, which may allow for transcriptional control by CLOCK:BMAL1 (Reddy et al. 2007), and can interact with PER2 (Schmutz et al. 2010)....

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  • ...NAD levels exhibit circadian oscillations in the liver, likely owing to transcriptional regulation of nicotinamide phosphoribosyltransferase (Nampt, encoding the rate-limiting enzyme in the NAD+ salvage pathway) by CLOCK:BMAL1 (Nakahata et al. 2009, Ramsey et al. 2009)....

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  • ...Other feedback loops involve the PAR-bZip family members, DBP, HLF, and TEF; the bZip protein, E4BP4 (Nfil3); and the bHLH proteins, DEC1 and DEC2 (Bhlhb2, Bhlhb3), all of which are transcriptional targets of CLOCK-BMAL1 (Gachon 2007, Lowrey & Takahashi 2004, Takahashi et al. 2008)....

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Journal ArticleDOI
03 Dec 2010-Science
TL;DR: Advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes are reviewed and implications for rational therapeutics for these conditions are reviewed.
Abstract: Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.

1,538 citations

Journal ArticleDOI
TL;DR: Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling.
Abstract: Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.

1,538 citations

References
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Journal ArticleDOI
23 Feb 2007-Cell
TL;DR: The surface of nucleosomes is studded with a multiplicity of modifications that can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA.

10,046 citations


"The NAD+-Dependent Deacetylase SIRT..." refers background in this paper

  • ...The remodeling of chromatin is largely elicited by enzyme-catalyzed posttranslational modifications of the core histone N-terminal tails (Kouzarides, 2007; Li et al., 2007a; Peterson and Laniel, 2004; Strahl and Allis, 2000)....

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  • ...Unique combinations of these modifications, for which the ‘‘histone code’’ hypothesis has been formulated (Strahl and Allis, 2000), induce conformational changes of chromatin, rendering it permissive to transcription, silencing, DNA replication, and repair (Cheung et al., 2000a; Kouzarides, 2007; Kurdistani and Grunstein, 2003; Li et al., 2007a; Strahl and Allis, 2000)....

    [...]

  • ...…hypothesis has been formulated (Strahl and Allis, 2000), induce conformational changes of chromatin, rendering it permissive to transcription, silencing, DNA replication, and repair (Cheung et al., 2000a; Kouzarides, 2007; Kurdistani and Grunstein, 2003; Li et al., 2007a; Strahl and Allis, 2000)....

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Journal ArticleDOI
06 Jan 2000-Nature
TL;DR: It is proposed that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.
Abstract: Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a 'histone code' that is, read by other proteins to bring about distinct downstream events.

8,265 citations


"The NAD+-Dependent Deacetylase SIRT..." refers background in this paper

  • ...The remodeling of chromatin is largely elicited by enzyme-catalyzed posttranslational modifications of the core histone N-terminal tails (Kouzarides, 2007; Li et al., 2007a; Peterson and Laniel, 2004; Strahl and Allis, 2000)....

    [...]

  • ...Unique combinations of these modifications, for which the ‘‘histone code’’ hypothesis has been formulated (Strahl and Allis, 2000), induce conformational changes of chromatin, rendering it permissive to transcription, silencing, DNA replication, and repair (Cheung et al., 2000a; Kouzarides, 2007; Kurdistani and Grunstein, 2003; Li et al., 2007a; Strahl and Allis, 2000)....

    [...]

  • ...Unique combinations of these modifications, for which the ‘‘histone code’’ hypothesis has been formulated (Strahl and Allis, 2000), induce conformational changes of chromatin, rendering it permissive to transcription, silencing, DNA replication, and repair (Cheung et al., 2000a; Kouzarides, 2007;…...

    [...]

  • ...…hypothesis has been formulated (Strahl and Allis, 2000), induce conformational changes of chromatin, rendering it permissive to transcription, silencing, DNA replication, and repair (Cheung et al., 2000a; Kouzarides, 2007; Kurdistani and Grunstein, 2003; Li et al., 2007a; Strahl and Allis, 2000)....

    [...]

  • ...Histone acetylation is recognized as one of the most prominent epigenetic marks leading to activation of gene expression (Strahl and Allis, 2000)....

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Journal ArticleDOI
15 Dec 2006-Cell
TL;DR: RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in P GC-1alpha acetylation and an increase in PGC-1 alpha activity.

3,740 citations


"The NAD+-Dependent Deacetylase SIRT..." refers background in this paper

  • ...…(Brunet et al., 2004; Luo et al., 2001), promotes mobilization of fat from white adipose tissues, an event that contributes to extending the life span (Picard et al., 2004), and mediates the metabolism of energy sources in metabolically active tissues (Lagouge et al., 2006; Rodgers et al., 2005)....

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  • ..., 2004), and mediates the metabolism of energy sources in metabolically active tissues (Lagouge et al., 2006; Rodgers et al., 2005)....

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Journal ArticleDOI
23 Feb 2007-Cell
TL;DR: This Review highlights advances in the understanding of chromatin regulation and discusses how such regulation affects the binding of transcription factors as well as the initiation and elongation steps of transcription.

3,424 citations


"The NAD+-Dependent Deacetylase SIRT..." refers background in this paper

  • ...The remodeling of chromatin is largely elicited by enzyme-catalyzed posttranslational modifications of the core histone N-terminal tails (Kouzarides, 2007; Li et al., 2007a; Peterson and Laniel, 2004; Strahl and Allis, 2000)....

    [...]

  • ...…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…...

    [...]

  • ...…hypothesis has been formulated (Strahl and Allis, 2000), induce conformational changes of chromatin, rendering it permissive to transcription, silencing, DNA replication, and repair (Cheung et al., 2000a; Kouzarides, 2007; Kurdistani and Grunstein, 2003; Li et al., 2007a; Strahl and Allis, 2000)....

    [...]

  • ...…et al., 2001; Vaziri et al., 2001), FOXO3 (Brunet et al., 2004; Motta et al., 2004), PGC-1a (Nemoto et al., 2005; Rodgers et al., 2005), and LXR (Li et al., 2007a), are regulated by SIRT1-mediated deacetylation, stressing the pivotal function that this regulator plays in cellular control and…...

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  • ...…groups of specific lysine residues in the N termini of core histones is generally associated with transcription activity, as it is thought to induce an open chromatin conformation that allows the transcription machinery access to promoters (Cheung et al., 2000a; Li et al., 2007a; Struhl, 1998)....

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Journal ArticleDOI
17 Feb 2000-Nature
TL;DR: The analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo, and provides a molecular framework of NAD-dependent histone de acetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.
Abstract: Yeast Sir2 is a heterochromatin component that silences transcription at silent mating loci, telomeres and the ribosomal DNA, and that also suppresses recombination in the rDNA and extends replicative life span. Mutational studies indicate that lysine 16 in the amino-terminal tail of histone H4 and lysines 9, 14 and 18 in H3 are critically important in silencing, whereas lysines 5, 8 and 12 of H4 have more redundant functions. Lysines 9 and 14 of histone H3 and lysines 5, 8 and 16 of H4 are acetylated in active chromatin and hypoacetylated in silenced chromatin, and overexpression of Sir2 promotes global deacetylation of histones, indicating that Sir2 may be a histone deacetylase. Deacetylation of lysine 16 of H4 is necessary for binding the silencing protein, Sir3. Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, which deacetylate lysines 9 and 14 of H3 and specifically lysine 16 of H4. Our analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo. These findings provide a molecular framework of NAD-dependent histone deacetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.

3,252 citations


"The NAD+-Dependent Deacetylase SIRT..." refers background or methods in this paper

  • ..., 2006), and also because SIRT1 deacetylase function was described to be targeted to these lysines (Imai et al., 2000)....

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  • ...We reasoned that CLOCK-mediated acetylation, and thereby transcriptional activation, could be counterbalanced by transcriptional silencing induced by NAD+-dependent HDACs (Imai et al., 2000; Landry et al., 2000)....

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  • ...This assay likely reflects the intracellular relative concentrations of NAD+ and NAM, or of yet undefined circadian metabolites, whose ratio determines SIRT1 activity (Imai et al., 2000; Luo et al., 2001)....

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  • ...We reasoned that CLOCK-mediated acetylation, and thereby transcriptional activation, could be counterbalanced by transcriptional silencing induced by NAD-dependent HDACs (Imai et al., 2000; Landry et al., 2000)....

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  • ...We analyzed the acetylation at Lys9 and Lys14 of histone H3 because we had previously found these to be preferential sites of CLOCK’s HAT activity (Doi et al., 2006), and also because SIRT1 deacetylase function was described to be targeted to these lysines (Imai et al., 2000)....

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