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Mistimed sleep disrupts circadian regulation of the human blood transcriptome

ABSTRACT: 22 healthy volunteers without sleep disorders were resident in an environmental scheduling facility and participated in a forced-desynchrony protocol, in which the sleep-wake cycle and the associated fasting-feeding cycle is scheduled to a 28-hour period, of which one third (i.e. 9h 20min) is scheduled for sleep. Under these conditions, during which light levels in the waking episode are kept low and sleep is scheduled in darkness, the phase of the melatonin rhythm occurred at approximately the same clock time during the first (D1) and fourth (D4) 28-h cycle and there were no major changes in either the amplitude or the waveform of this rhythm. During D1 and D4 7 blood samples were taken, RNA was extracted from leukocytes, labelled and hybridised to human whole-genome microarrays

ORGANISM(S): Homo sapiens

PROVIDER: GSE48113 | GEO | 2014/01/23

SECONDARY ACCESSION(S): PRJNA208941

REPOSITORIES: GEO

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Project description:Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. To identify the genes responsible for the protective effects of starvation we conducted transcription profiling of sleep deprived flies that accrue sleep debt compared to starved siblings that do not. Genes involved in lipid metabolism were highly enriched in our dataset of 84 differentially regulated transcripts. Follow up genetic studies established that 6 genes involved in lipid metabolism strongly influence sleep homeostasis. Two of these genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), are in the same lipolysis pathway but exert antagonistic effects on lipid storage. bmm mutant flies have excess fat stores and display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking. Two-condition experiments: sleep deprived vs starved. RNA from 8 biological replicates for each condition was pooled in groups of 2 to create 4 samples. Each of the 4 samples is run in duplicate with untreated circadian matched controls.