Mammalian Circadian Clock: The Roles of Transcriptional Repression and Delay
The circadian clock is an endogenous oscillator with a 24-h period. Although delayed feedback repression was proposed to lie at the core of the clock more than 20 years ago, the mechanism for making delay in feedback repression in clock function has only
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Abstract The circadian clock is an endogenous oscillator with a 24-h period. Although delayed feedback repression was proposed to lie at the core of the clock more than 20 years ago, the mechanism for making delay in feedback repression in clock function has only been demonstrated recently. In the mammalian circadian clock, delayed feedback repression is mediated through E/E0 -box, D-box, and RRE transcriptional cis-elements, which activate or repress each other through downstream transcriptional activators/repressors. Among these three types of cis-elements, transcriptional negative feedback mediated by E/E0 -box plays a critical role for circadian rhythms. A recent study showed that a combination of D-box and RRE elements results in the delayed expression of Cry1, a potent transcriptional inhibitor of the E/E0 -box. The overall interconnection of these cis-elements can be summarized as a combination of two oscillatory motifs: one is a simple delayed feedback repression where only an RRE represses an E/E0 -box, and the other is a repressilator where each element inhibits another in turn (i.e., E/E0 box represses an RRE, an RRE represses a D-box, and a D-box represses an E/E0 box). Experimental verification of the roles of each motif as well as post-transcriptional regulation of the circadian oscillator will be the next challenges.
Y. Minami Laboratory for Systems Biology, Center for Developmental Biology, RIKEN, Chuo-ku, Kobe, Hyogo, Japan 650-0047 K.L. Ode Laboratory for Synthetic Biology, Quantitative Biology Center, RIKEN, Chuo-ku, Kobe, Hyogo, Japan 650-0047 H.R. Ueda (*) Laboratory for Systems Biology, Center for Developmental Biology, RIKEN, Chuo-ku, Kobe, Hyogo, Japan 650-0047 Laboratory for Synthetic Biology, Quantitative Biology Center, RIKEN, Chuo-ku, Kobe, Hyogo, Japan 650-0047 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_15, # Springer-Verlag Berlin Heidelberg 2013
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Keywords Phase vector model • Time delay • Clock controlled cis elements
1 Circadian Clock in Mammals In mammals the master clock is located in the suprachiasmatic nucleus (SCN). Transcript analyses have indicated that circadian clocks are not restricted to SCN, but are found in several tissues including the liver (Yamazaki et al. 2000) and cultured cells such as rat fibroblasts Rat-1 (Balsalobre et al. 1998), mouse fibroblasts NIH3T3 (Tsuchiya et al. 2003), or human osteosarcoma U-2OS cells (Isojima et al. 2009; Vollmers et al. 2008). Therefore, circadian rhythms are driven by cell-autonomous oscillators. Studies across species have elucidated the conserved feature of molecular mechanisms underlying circadian rhythms: at the core of the clock lies a transcriptional/translational negative feedback loop. For example, in mice the transcription factors CLOCK and BMAL1 dimerize and activate transcription of the Per and Cry genes. PER and CRY proteins accumulate in the cytosol become phosphorylated and return
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