MCB Accepts, published online ahead of print on 14 April 2008

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Mol. Cell. Biol. doi:10.1128/MCB.02168-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

DEC1 modulates circadian phase of clock gene expression

Ayumu Nakashima, Takeshi Kawamoto^*, Kiyomasa K. Honda, Taichi Ueshima, Mitsuhide Noshiro, Tomoyuki Iwata, Katsumi Fujimoto, Hiroshi Kubo, Sato Honma, Noriaki Yorioka, Nobuoki Kohno, and Yukio Kato^*

Department of Dental and Medical Biochemistry, Department of Molecular and Internal Medicine, Department of Periodontal Medicine, and Department of Advanced Nephrology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima 734-8551, Japan; Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; Japan science and technology agency, JST innovation plaza Hiroshima, Higashi-Hiroshima 739-0046, Japan

^* To whom correspondence should be addressed. Email: tkawamo{at}hiroshima-u.ac.jp. ykato{at}hiroshima-u.ac.jp.

DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E-boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E'-boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes, but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E-box, but not on the E'-box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1^-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under constant darkness, and faster re-entrainment to 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with siRNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.

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