The Epigenetic Language of Circadian Clocks
Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Remodeling of chromatin constitutes a critical interface of transducing signals, such as light or nutrient availabil
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Abstract Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Remodeling of chromatin constitutes a critical interface of transducing signals, such as light or nutrient availability, and how these are interpreted by the cell to generate permissive or silenced states for transcription. CLOCK-BMAL1-mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Here we will discuss the evidence demonstrating that chromatin remodeling is at the crossroads of circadian rhythms and regulation of metabolism and cellular proliferation. Keywords Circadian clock • Epigenetics • Histone modifications • Sirtuins
1 Introduction Circadian rhythms occur with a periodicity of about 24 h and regulate a wide array of metabolic and physiologic functions. Accumulating epidemiological and genetic evidence indicates that disruption of circadian rhythms can be directly linked to many pathological conditions, including sleep disorders, depression, metabolic
S. Sahar • P. Sassone-Corsi (*) Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine, CA 92697, USA e-mail: [email protected] A. Kramer and M. Merrow (eds.), Circadian Clocks, Handbook of Experimental Pharmacology 217, DOI 10.1007/978-3-642-25950-0_2, # Springer-Verlag Berlin Heidelberg 2013
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syndrome, and cancer. Intriguingly, a number of molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of cellular metabolism and cell cycle. The Earth’s rotation around its axis leads to day–night cycles, which affects the physiology of most living organisms. Circadian (from the Latin circa diem meaning “about a day”) clocks are intrinsic, time-tracking systems that enable organisms to anticipate environmental changes (such as food availability and predatory pressure) and allow them to adapt their behavior and physiology to the appropriate time of day (Schibler and Sassone-Corsi 2002). Feeding behavior, sleep–wake cycles, hormonal levels, and body temperature are just a few examples of physiological circadian rhythms, with light being the principal zeitgeber (“time giver”). Other zeitgebers, such as feeding time and temperature, are discussed in accompanying chapters in this book (Brown and Azzi 2013; Buhr and Takahashi 2013). The three integral parts of circadian clocks are the following: an input pathway that includes detectors to receive environmental cues (or zeitgebers) and transmits them to the cen
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