A novel E4BP4 element drives circadian expression of mPeriod2

Dec 22, 2006Nucleic acids research

A new DNA element controls daily timing of mPeriod2 gene activity

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Abstract

E4BP4 is required for the negative regulation of circadian expression of Per2.

E4BP4 negatively regulates Per2 mRNA oscillation in the cell-autonomous clock.
Two putative E4BP4-binding sites were identified on the Per2 promoter, termed A-site and B-site.
The B-site is responsible for E4BP4-mediated transcriptional repression of Per2.
E4BP4 binding peaks at the B-site coincide with the trough of Per2 mRNA expression.
Both the B-site and the E2 enhancer are necessary for robust circadian expression of Per2.

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Period2 (Per2) is an essential component of the mammalian clock mechanism and robust circadian expression of Per2 is essential for the maintenance of circadian rhythms. Although recent studies have shown that the circadian E2 enhancer (a non-canonical E-box) accounts for most of the circadian transcriptional drive of mPer2, little is known about the other cis-elements of mPer2 oscillatory transcription. Here, we examined the contribution of E4BP4 to Per2 mRNA oscillation in the cell-autonomous clock. Knockdown experiments of E4BP4 in both Northern blots and real-time luciferase assays suggested that endogenous E4BP4 negatively regulates Per2 mRNA oscillation. Sequence analysis revealed two putative E4BP4-binding sites (termed A-site and B-site) on mammalian Per2 promoter regions. Luciferase assays with mutant constructs showed that a novel E4BP4-binding site (B-site) is responsible for E4BP4-mediated transcriptional repression of Per2. Furthermore, chromatin immunoprecipitation assays in vivo showed that the peak of E4BP4 binding to the B-site on the Per2 promoter almost matched the trough of Per2 mRNA expression. Importantly, real-time luciferase assays showed that the B-site in addition to the E2 enhancer is required for robust circadian expression of Per2 in the cell-autonomous clock. These findings indicated that E4BP4 is required for the negative regulation of mammalian circadian clocks.

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A novel E4BP4 element drives circadian expression of mPeriod2

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