A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation

Abstract

An autofeedback loop associated with transcription of clock gene(s), Per(s), is generally accepted as the molecular machinery of circadian rhythm generation, in which CLOCK/BMAL act as positive regulators and PER/CRY as negative ones. We show here an autofeedback loop of Dec1 encoding a basic helix-loop-helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription. Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression. The level of Dec1 expression in the heart of Clock/Clock mutant mice was continuously low throughout the day. These findings suggest that Dec1 is positively regulated by CLOCK/BMAL and is involved in circadian rhythm regulation by suppressing CLOCK/BMAL-induced gene expression. The autofeedback loop of Dec1 may be interlocked with the core feedback loop of Per in some situations.