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Commun Biol. 2019 Aug 8;2:300. doi: 10.1038/s42003-019-0522-3. eCollection 2019.

Functional D-box sequences reset the circadian clock and drive mRNA rhythms.

Author information

1Department of Biological Sciences, School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku Tokyo, 113-0033 Japan.
2Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwanoha 5-1-5,, Kashiwa Chiba, 277-8568 Japan.
3Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida-Shimo-Adachi-cho 46-29, Kyoto, 606-8501 Japan.
4Bioinformatics Laboratory, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575 Japan.
5Center for Artificial Intelligence Research, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8577 Japan.
Contributed equally


The circadian clock drives gene expression rhythms, leading to daily changes in physiology and behavior. In mammals, Albumin D-site-Binding Protein (DBP) rhythmically activates transcription of various genes through a DNA cis-element, D-box. The DBP-dependent transactivation is repressed by competitive binding of E4BP4 to the D-box. Despite the elaborate regulation, physiological roles of the D-box in the circadian clockwork are still elusive. Here we identified 1490 genomic regions recognized commonly by DBP and E4BP4 in the mouse liver. We comprehensively defined functional D-box sequences using an improved bioinformatics method, MOCCS2. In RNA-Seq analysis of E4bp4-knockout and wild type liver, we showed the importance of E4BP4-mediated circadian repression in gene expression rhythms. In addition to the circadian control, we found that environmental stimuli caused acute induction of E4BP4 protein, evoking phase-dependent phase shifts of cellular circadian rhythms and resetting the clock. Collectively, D-box-mediated transcriptional regulation plays pivotal roles in input and output in the circadian clock system.


Circadian mechanisms; Circadian rhythms; Gene regulation

Conflict of interest statement

Competing interestsThe authors declare no competing interests.

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