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 been demonstrated recently. In the mammalian circadian clock, delayed feedback repression is mediated through E/E'-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/E'-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/E'-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/E'-box, and the other is a repressilator where each element inhibits another in turn (i.e., E/E' box represses an RRE, an RRE represses a D-box, and a D-box represses an E/E' box). Experimental verification of the roles of each motif as well as post-transcriptional regulation of the circadian oscillator will be the next challenges.