DEC2 modulates orexin expression and regulates sleep

Arisa Hirano, Pei Ken Hsu, Luoying Zhang, Lijuan Xing, Thomas McMahon, Maya Yamazaki, Louis J. Ptáček*, Ying Hui Fu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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. Themutant DEC2 has less repressor activity thanWT-DEC2, resulting in increased orexin expression. DEC2-binding affinity for the preproorexin gene promoter is decreased by the P384Rmutation, likely due toweakened interactionwith 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.

Original languageEnglish (US)
Pages (from-to)3434-3439
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number13
DOIs
StatePublished - Mar 27 2018

Keywords

  • Behavior
  • Genetics
  • Mouse model
  • Sleep

ASJC Scopus subject areas

  • General

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