1. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1.
- Author
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Bellet, Marina M., Nakahata, Yasukazu, Boudjelai, Mohamed, Watts, Emma, Mossakowska, Danuta E., Edwards, Kenneth A., Cervantes, Marlene, Astarita, Giuseppe, Loh, Christine, Ellis, James L., Vlasuk, George P., and Sassone-Corsi, Paolo
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DEACETYLASES , *ELECTRIC rheostats , *LABORATORY mice , *GENE expression , *SIRTUINS , *HISTONE acetyltransferase - Abstract
Circadian rhythms govern a wide variety of physiological and metabolic functions in many organisms, from prokaryotes to humans. We previously reported that silent information regulator 1 (SIRT1), a NAD+-dependent deacetylase, contributes to circadian control. In addition, SIRT1 activity is regulated in a cyclic manner in virtue of the circadian oscillation of the coenzyme NAD+. Here we used specific SIRT1 activator compounds both in vitro and in vivo. We tested a variety of compounds to show that the activation of SIRT1 alters CLOCK:BMAL1-driven transcription in different systems. Activation of SIRT1 induces repression of circadian gene expression and decreases H3 K9/K14 acetylation at corresponding promoters in a time-specific manner. Specific activation of SIRT1 was demon- strated in vivo using liver-specific SIRT1-deficient mice, where the effect of SIRT1 activator compounds was shown to be dependent on SIRT1. Our findings demonstrate that SIRT1 can fine-tune circadian rhythm and pave the way to the development of pharmacological strategies to address a broad range of therapeutic indications. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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