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Nat Commun. 2019 Jun 12;10(1):2563. doi: 10.1038/s41467-019-10532-2.

Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity.

Author information

1
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyō-ku, Kyoto, 606-8501, Japan. doimasao@pharm.kyoto-u.ac.jp.
2
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyō-ku, Kyoto, 606-8501, Japan.
3
Laboratory of Molecular Brain Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyō-ku, Kyoto, 606-8501, Japan.
4
Laboratories for Animal Resource Development and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan.
5
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
6
Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
7
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
8
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyō-ku, Kyoto, 606-8501, Japan. okamurah@pharm.kyoto-u.ac.jp.
9
Laboratory of Molecular Brain Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyō-ku, Kyoto, 606-8501, Japan. okamurah@pharm.kyoto-u.ac.jp.

Abstract

Non-coding cis-regulatory elements are essential determinants of development, but their exact impacts on behavior and physiology in adults remain elusive. Cis-element-based transcriptional regulation is believed to be crucial for generating circadian rhythms in behavior and physiology. However, genetic evidence supporting this model is based on mutations in the protein-coding sequences of clock genes. Here, we report generation of mutant mice carrying a mutation only at the E'-box cis-element in the promoter region of the core clock gene Per2. The Per2 E'-box mutation abolishes sustainable molecular clock oscillations and renders circadian locomotor activity and body temperature rhythms unstable. Without the E'-box, Per2 messenger RNA and protein expression remain at mid-to-high levels. Our work delineates the Per2 E'-box as a critical nodal element for keeping sustainable cell-autonomous circadian oscillation and reveals the extent of the impact of the non-coding cis-element in daily maintenance of animal locomotor activity and body temperature rhythmicity.

PMID:
31189882
PMCID:
PMC6561950
DOI:
10.1038/s41467-019-10532-2
[Indexed for MEDLINE]
Free PMC Article

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