A signalling pathway for transcriptional regulation of sleep amount in mice

Rui Zhou, Guodong Wang, Qi Li, Fanxi Meng, Can Liu, Rui Gan, Dapeng Ju, Meimei Liao, Junjie Xu, Di Sang, Xue Gao, Shuang Zhou, Kejia Wu, Quanzhi Sun, Ying Guo, Chongyang Wu, Zhiyu Chen, Lin Chen, Bihan Shi, Haiyan Wang, Xia Wang, Huaiye Li, Tao Cai, Bin Li, Fengchao Wang, Hiromasa Funato, Masashi Yanagisawa, Eric Erquan Zhang and Qinghua Liu ()
Additional contact information
Rui Zhou: China Agriculture University
Guodong Wang: National Institute of Biological Sciences, Beijing (NIBS)
Qi Li: National Institute of Biological Sciences, Beijing (NIBS)
Fanxi Meng: National Institute of Biological Sciences, Beijing (NIBS)
Can Liu: National Institute of Biological Sciences, Beijing (NIBS)
Rui Gan: National Institute of Biological Sciences, Beijing (NIBS)
Dapeng Ju: Chongqing Medical University
Meimei Liao: China Agriculture University
Junjie Xu: National Institute of Biological Sciences, Beijing (NIBS)
Di Sang: National Institute of Biological Sciences, Beijing (NIBS)
Xue Gao: National Institute of Biological Sciences, Beijing (NIBS)
Shuang Zhou: National Institute of Biological Sciences, Beijing (NIBS)
Kejia Wu: National Institute of Biological Sciences, Beijing (NIBS)
Quanzhi Sun: National Institute of Biological Sciences, Beijing (NIBS)
Ying Guo: National Institute of Biological Sciences, Beijing (NIBS)
Chongyang Wu: National Institute of Biological Sciences, Beijing (NIBS)
Zhiyu Chen: National Institute of Biological Sciences, Beijing (NIBS)
Lin Chen: National Institute of Biological Sciences, Beijing (NIBS)
Bihan Shi: National Institute of Biological Sciences, Beijing (NIBS)
Haiyan Wang: National Institute of Biological Sciences, Beijing (NIBS)
Xia Wang: National Institute of Biological Sciences, Beijing (NIBS)
Huaiye Li: National Institute of Biological Sciences, Beijing (NIBS)
Tao Cai: National Institute of Biological Sciences, Beijing (NIBS)
Bin Li: National Institute of Biological Sciences, Beijing (NIBS)
Fengchao Wang: National Institute of Biological Sciences, Beijing (NIBS)
Hiromasa Funato: Toho University
Masashi Yanagisawa: University of Tsukuba
Eric Erquan Zhang: National Institute of Biological Sciences, Beijing (NIBS)
Qinghua Liu: National Institute of Biological Sciences, Beijing (NIBS)

Nature, 2022, vol. 612, issue 7940, 519-527

Abstract: Abstract In mice and humans, sleep quantity is governed by genetic factors and exhibits age-dependent variation1–3. However, the core molecular pathways and effector mechanisms that regulate sleep duration in mammals remain unclear. Here, we characterize a major signalling pathway for the transcriptional regulation of sleep in mice using adeno-associated virus-mediated somatic genetics analysis4. Chimeric knockout of LKB1 kinase—an activator of AMPK-related protein kinase SIK35–7—in adult mouse brain markedly reduces the amount and delta power—a measure of sleep depth—of non-rapid eye movement sleep (NREMS). Downstream of the LKB1–SIK3 pathway, gain or loss-of-function of the histone deacetylases HDAC4 and HDAC5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Moreover, phosphorylation of HDAC4 and HDAC5 is associated with increased sleep need, and HDAC4 specifically regulates NREMS amount in posterior hypothalamus. Genetic and transcriptomic studies reveal that HDAC4 cooperates with CREB in both transcriptional and sleep regulation. These findings introduce the concept of signalling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate the power of somatic genetics in mouse sleep research.

Date: 2022
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DOI: 10.1038/s41586-022-05510-6

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