DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated transcription regulation of the circadian gene mPer1

Jun 15, 2004The Biochemical journal

DEC1 controls daily gene mPer1 by binding DNA, not by interacting with Bmal1

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Abstract

DEC1 and DEC2 proteins repress the mPer1 promoter primarily through E-box binding, rather than interaction with Bmal1.

E-box binding is crucial for the repression of the mPer1 promoter by DEC1 and DEC2.
In the absence of Clock/Bmal1, DEC1 and DEC2 still significantly repress the mPer1 promoter.
DNA-binding mutants of DEC1 and DEC2 exhibit no repressive activity, confirming the importance of DNA binding.
DEC1(R58P), which can interact with Bmal1, fails to repress the mPer1 promoter, highlighting that Bmal1 interaction is not responsible for repression.
The disruption of the Sp1 site in the mPer1 promoter enhances the repression by DEC1 proteins.
Altered expression of DEC genes may influence circadian rhythms and is linked to the development of various diseases, including cancer.

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DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors and exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved by binding to E-box elements and interacting with Bmal1. In the present study, we report that E-box binding rather than Bmal1 interaction is responsible for the observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the Clock/Bmal1-induced activation, providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2 showed that this factor interacts with Sp1. These findings suggest that DEC proteins regulate the expression of mPer1 through E-box binding and Sp1 interaction. Alterations on circadian systems are increasingly recognized as important risk factors for disease initiation and progression, and the expression of Dec genes is rapidly induced by environmental stimuli and is highly increased in tumour tissues. Therefore de-regulated expression of DEC genes probably alters normal circadian rhythms and contributes significantly to the pathogenesis of many diseases including cancer.

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DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated transcription regulation of the circadian gene mPer1

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