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Contributed by Louis J. Ptáček, February 12, 2018 (sent for review December 4, 2017; reviewed by Ken-ichi Honma and Toru Takumi)
Significance
Sleep is essential for healthy aging, and most people need approximately 8–8-1/2 hours of sleep per night to feel good and to function optimally. We previously reported a proline-to-arginine mutation in DEC2 that leads to a life-long decrease in daily sleep need. We found that the expression of an important sleep-relevant gene, orexin, was increased in the DEC2 mutant mice. Further investigation revealed that DEC2 is a transcriptional repressor for orexin expression, and that mutant DEC2 exerts less repressor activity than WT-DEC2, resulting in increased orexin expression. This study represents the first step toward understanding the underlying molecular mechanism through which DEC2 modulates sleep.
Abstract
Adequate sleep is essential for physical and mental health. We previously identified a missense mutation in the human DEC2 gene (BHLHE41) leading to the familial natural short sleep behavioral trait. DEC2 is a transcription factor regulating the circadian clock in mammals, although its role in sleep regulation has been unclear. Here we report that prepro-orexin, also known as hypocretin (Hcrt), gene expression is increased in the mouse model expressing the mutant hDEC2 transgene (hDEC2-P384R). Prepro-orexin encodes a precursor protein of a neuropeptide producing orexin A and B (hcrt1 and hcrt2), which is enriched in the hypothalamus and regulates maintenance of arousal. In cell culture, DEC2 suppressed prepro-orexin promoter-luc (ore-luc) expression through cis-acting E-box elements. The mutant DEC2 has less repressor activity than WT-DEC2, resulting in increased orexin expression. DEC2-binding affinity for the prepro-orexin gene promoter is decreased by the P384R mutation, likely due to weakened interaction with other transcription factors. In vivo, the decreased immobility time of the mutant transgenic mice is attenuated by an orexin receptor antagonist. Our results suggested that DEC2 regulates sleep/wake duration, at least in part, by modulating the neuropeptide hormone orexin.
Footnotes
↵1Present address: College of Life Science and Technology and the collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
- ↵2To whom correspondence may be addressed. Email: ljp{at}ucsf.edu or Ying-Hui.fu{at}ucsf.edu.
Author contributions: A.H., L.J.P., and Y.-H.F. designed research; A.H., P.-K.H., L.Z., L.X., T.M., and M.Y. performed research; A.H. analyzed data; and A.H., L.J.P., and Y.-H.F. wrote the paper.
Reviewers: K.-i.H., Hokkaido University Graduate School of Medicine; and T.T., RIKEN Brain Science Institute.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1801693115/-/DCSupplemental.
Published under the PNAS license.
DEC2 modulates orexin expression and regulates sleep
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