A signaling pathway for transcriptional regulation of sleep amount in mice
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ABSTRACT:
PROVIDER: PRJNA758275 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR15652100_1.fastq.gz | Fastqsanger.gz | |||
| SRR15652100_2.fastq.gz | Fastqsanger.gz | |||
| SRR15652101_1.fastq.gz | Fastqsanger.gz | |||
| SRR15652101_2.fastq.gz | Fastqsanger.gz | |||
| SRR15652102_1.fastq.gz | Fastqsanger.gz |
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Project description:In mice and humans, sleep quantity of individuals are governed by genetic factors and exhibit age-dependent variations. However, the core molecular pathways and effector mechanisms that regulate sleep time in mammals remain unclear. Here, we characterize a major signaling pathway for transcriptional regulation of sleep quantity in mice by adeno-associated virus-mediated somatic genetics analysis. Adult brain chimeric-knockout of LKB1 kinase, an activator of AMPK-related protein kinase SIK3/SLEEPY, markedly reduces non-rapid eye movement sleep (NREMS) amount and delta power–a measure of sleep depth. Downstream of LKB1-SIK3 pathway, gain or loss-of-function of histone deacetylases HDAC4/5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Phosphorylation of HDAC4/5 is regulated in relation to sleep need, and HDAC4 specifically regulates sleep 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 signaling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate utility of somatic genetics in mouse sleep research.
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Project description:Different mammalian species vary greatly in their daily sleep quota, ranging from 2-4 hours in giraffes to 20-22 hours in koalas and bats. In humans, the sleep quantity and quality of individuals are governed by genetic factors and exhibit age-dependent variations. However, the molecular pathways and effector mechanisms that regulate daily sleep need in mammals remain unknown. Here, using an adult brain chimeric (ABC)-expression/knockout (KO) system for somatic genetics analysis of sleep in adult mice, we report that gain-of-function of histone deacetylases HDAC4/5 significantly reduces, whereas loss-of-function of HDAC4/5 increases daily non-rapid eye movement sleep (NREMS) amount and delta power–two key indicators of sleep need. Similarly, ABC-expression of cAMP-response element binding protein (CREB) or A-CREB, an inhibitor of transcriptional activity of CREB, decreases or increases NREMS amount and delta power, respectively. A combination of genetic and transcriptomic analysis reveals that HDAC4 functions in tandem with CREB in both transcriptional and sleep regulation. Consistent with their functions downstream of LKB1-SIK3 kinase cascade, ABC-expression of HDAC4/5CA or CREB rescues hypersomnia of Sik3E13∆/+ mice, whereas ABC-expression of SIK3/SLP-ST221E or HDAC(4+5)VP16 rescues insomnia of ABC-Lkb1KO mice. Taken together, these results identify LKB1-SIK3-HDAC4/5-CREB as the first major molecular pathway for transcriptional regulation of daily sleep need in mammals.
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Project description:A molecular pathway for transcriptional regulation of daily sleep need in mice
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