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

By Yasukazu Nakahata, M. Kaluzová, B. Grimaldi, Saurabh Sahar, J. Hirayama, Danica Chen, L. Guarente, Paolo Sassone-Corsi. Cell, 2008

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SUMMARY Circadian rhythms govern a large array of metabolic and physiological functions. The central clock protein CLOCK has HAT properties. It directs acetylation of histone H3 and of its dimerization partner BMAL1 at Lys537, an event essential for circadian function. We show that the HDAC activity of the NAD+-dependent SIRT1 enzyme is regulated in a circadian manner, correlating with rhythmic acetylation of BMAL1 and H3 Lys9/Lys14 at circadian promoters. SIRT1 associates with CLOCK and is recruited to the CLOCK:BMAL1 chromatin complex at circadian promoters. Genetic ablation of the Sirt1 gene or pharmacological inhibition of SIRT1 activity lead to disturbances in the circadian cycle and in the acetylation of H3 and BMAL1. Finally, using liver-specific SIRT1 mutant mice we show that SIRT1 contributes to circadian control in vivo. We propose that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock.

Subfields: Endocrine and Autonomic Systems, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9d01508b7becf5cdf3c68f2ead76ae34cc680315

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Citations in the corpus

SIRT1 and other sirtuins in Metabolism (2013, background): “Finally, SIRT1 plays an important role in maintaining circadian regulation of metabolic processes in the liver by regulating the cell-autonomous, circadian clock in that tissue [69,70].”
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RNA-methylation-dependent RNA processing controls the speed of the circadian clock. (2013, positive): “Metabolism in turn can adjust the clock, for example by modulating acetylation/deacetylation of histones on promoters activated by core clock protein complex CLOCK:ARNTL (Nakahata et al., 2008) or directly by affecting acetylation status of PER proteins (Asher et al., 2008).”
Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations. (2016, positive): “…products serve as an important input into the circadian clock network, thereby creating a bi-directional feedback loop of reciprocal control between cellular metabolic activity and the circadian clock (Asher et al., 2008; Nakahata et al., 2008, 2009; Ramsey et al., 2009; Zwighaft et al., 2015).”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “SIRT1 induces the circadian transcription of core clock genes, such as Cry1, Per2, Rorγ, and Bmal1 via either rhythmically deacetylating BMAL1 or PER2.”
Timing to perfection: the biology of central and peripheral circadian clocks. (2012, background): “This enzyme physically interacts with BMAL1/CLOCK heterodimers, leading to a rhythmic deacetylation of BMAL1, histone H3 (Nakahata et al., 2008), and PER2 (Asher et al., 2008).”
The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease (2008, background): “The histone deacetylase sirtuin 1 (SIRT1) interacts with CLOCK and can deacetylate lysine 537 of BMAL1 as well as lysine 9 and 14 of histone H3 (Ref”
Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “, 2007b), and that NAD diminution directly inactivates SIRT1 (Nakahata et al., 2008).”