CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP

DBP, the founding member of the PAR leucine zipper transcription factor fam ily, is expressed according to a robust daily rhythm in the suprachiasmatic nucleus and several peripheral tissues. Previous studies with mice deleted for the Dbp gene have established that DBP participates in the regulation of several clock outputs, including locomotor activity, sleep distribution, and liver gene expression. Here we present evidence that circadian Dbp tra nscription requires the basic helix-loop-helix-PAS protein CLOCK, an essent ial component of the negative-feedback circuitry generating circadian oscil lations in mammals and fruit flies. Genetic and biochemical experiments sug gest that CLOCK regulates Dbp expression by binding to E-box motifs within putative enhancer regions located in the first and second introns. Similar E-box motifs have been found previously in the promoter sequence of the mur ine clock gene mPeriod1. Hence, the same molecular mechanisms generating ci rcadian oscillations in the expression of clock genes may directly control the rhythmic transcription of clock output regulators such as Dbp.