The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator

As the period length of this pacemaker is only approximately 24 hr, the circadian clock has to be reset every day by an input pathway in order to remain in resonance with geophysical time. This synchronization Division of Biochemistry Animal circadian rhythms appear to be generated by University of Fribourg feedback loops in gene expression that include both Rue du Musé e 5 transcriptional and posttranscriptional regulatory mech-CH 1700 Fribourg anisms (Allada et al., 2001; Albrecht, 2002). In mammals, Switzerland the PAS helix-loop-helix transcription factors CLOCK and BMAL1 activate transcription of Per and Cry genes. Once the PER and CRY proteins have reached a critical Summary concentration, they attenuate the CLOCK/BMAL1-mediated activation of their own genes in a negative feedback Mammalian circadian rhythms are generated by a loop. A recent study suggests that the PER/CRY com-feedback loop in which BMAL1 and CLOCK, players plex interacts directly with the CLOCK/BMAL1 complex of the positive limb, activate transcription of the cryp-bound to chromatin. In addition, a number of posttrans-tochrome and period genes, components of the nega-lational events, such as the control of protein phosphor-tive limb. Bmal1 and Per transcription cycles display ylation, degradation, and nuclear entry, contribute criti-nearly opposite phases and are thus governed by dif-cally to the generation of daily oscillations in clock gene ferent mechanisms. Here, we identify the orphan nu-products (see Lee et al., 2001, and references therein). clear receptor REV-ERB␣ as the major regulator of Whereas a large body of genetic and biochemical cyclic Bmal1 transcription. Circadian Rev-erb␣ ex-evidence has been collected on the regulation of Cry pression is controlled by components of the general and Per gene expression, much less is known about the feedback loop. Thus, REV-ERB␣ constitutes a molecu-control of Bmal1 and Clock expression. Bmal1 mRNA lar link through which components of the negative accumulation also follows a robust circadian oscillation, limb drive antiphasic expression of components of the but this cycle is nearly antiphase to that of Per1 and positive limb. While REV-ERB␣ influences the period Per2 mRNA accumulation (Shearman et al., 2000b). In length and affects the phase-shifting properties of the the liver, Clock transcript levels fluctuate during the day clock, it is not required for circadian rhythm gener-with a phase angle similar to that of Bmal1 mRNA accu-ation. mulation, albeit with a modest amplitude of only 2-or 3-fold (Lee et al., 2001; this study). Given the large phase Introduction difference of cyclic …