Transcriptional control of circadian hormone synthesis via the CREM feedback loop.

Transcription factor cAMP-responsive element modulator (CREM) plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. The use of an alternative, intronic promoter within the CREM gene is responsible for the production of a cAMP-inducible repressor, inducible cAMP early repressor (ICER). ICER negatively autoregulates the ICER promoter, thus generating a feedback loop. We have previously documented a striking, clock-driven circadian fluctuation of CREM expression in the pineal gland. Oscillating ICER levels tightly correlate with fluctuations in the synthesis of the pineal hormone melatonin, whose production is also driven by the endogenous clock. Melatonin in turn regulates the hypothalamic-pituitary axis. The enzyme serotonin N-acetyltransferase (NAT) catalyzes the rate limiting step in melatonin synthesis. Thus, oscillations in NAT levels determine the circadian synthesis of melatonin. Here we demonstrate that NAT expression is dramatically increased in CREM-deficient mice that we have generated by homologous recombination. Characterization of the NAT promoter shows the presence of a ICER binding site. In addition, transfection studies show that ICER powerfully represses NAT transcription. Our results implicate CREM as a central regulator of output functions of the clock. Indeed, CREM acts as a key regulator of oscillatory hormonal synthesis.