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Transcriptional signatures of sleep duration discordance in monozygotic twins

ABSTRACT: Short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (e.g., genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of short habitual sleep duration on gene expression. Therefore, we sought to investigate gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD=18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with two-weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Next, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. The mean 24 hour sleep duration of the total sample was 439.2 minutes (SD=46.8 minutes; range 325.4 to 521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD=21.2; range 45.9 to 114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular and inflammatory outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80612 | GEO | 2016/09/09

SECONDARY ACCESSION(S): PRJNA319488

REPOSITORIES: GEO

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Project description:Introduction: Sleep deprivation is associated with increased cardiovascular risk, which is more pronounced in women than men; however, causal evidence is lacking and the underlying mechanisms are unclear. We used randomized crossover design of prolonged sleep deprivation that mimics “life-like conditions” and endothelial cells (ECs) harvested from healthy women to investigate directly whether sleep deprivation impairs endothelial function and to identify underlying mechanisms. Methods: Healthy women with normal habitual sleep (7-9 h/day) were randomly allocated to 6-weeks of adequate sleep (7-9 h/day) or sleep deprivation (1.5 h less than habitual sleep) in a crossover design. Sleep duration was monitored objectively by actigraphy. EC harvesting and brachial artery flow-mediated dilation (FMD) were performed at baseline and the end of adequate sleep and sleep deprivation period. Results: Twenty-eight healthy women (mean [SE] age 35±13 years; BMI 25±3 kg/m2) participated. Compared with adequate sleep, sleep deprivation reduced FMD (mean±SE 8.65±0.48 vs. 7.35±0.39, p=0.02) and increased EC inflammation (nuclear factor-κB nuclear fluorescence area mean±SE 1.36±0.24 vs. 2.04±0.38 μm2, p=0.03 and mRNA expression of vascular cell adhesion molecule-1 mean±SE 1.00±0.19 vs. 2.31±0.72, p=0.04) compared with adequate sleep. Sleep deprivation increased EC oxidative stress by 67% compared with adequate sleep (redox sensitive fluorogenic probe fluorescence intensity, p=0.002) without upregulating antioxidant response. Using RNA-seq and a predicted protein-protein interaction algorithm, we identified reduced expression of serum response factor, a transcription factor that primes cortical response to sleep deprivation, and its endothelial target Defective in Cullin Neddylation-1 Domain Containing 3 as novel mediators of impaired nuclear factor (erythroid-derived 2)-like 2-mediated antioxidant responses in ECs in sleep deprivation. Conclusion: Sleep deprivation impairs clearance of endothelial oxidant stress accumulated during wakefulness leading to endothelial dysfunction and potentially increased cardiovascular risk in women. Trial Registration Number: ClinicalTrials.gov NCT02835261

Project description:Sleep is essential for life. A good night's sleep is pleasurable and sleep deprivation is stressful. Prolonged sleep loss impairs temperature control, metabolism, immunity, and ultimately leads to death. Extensive observational and epidemiological evidence indicates that optimal sleep duration of 8 hours is associated with the maintenance of good health. In our society, however, most people only get 6.5 - 7 hours. Suboptimal sleep duration has a strong association with mortality and morbidity. Lack of sleep has been linked to cardiovascular diseases, obesity, hypertension, type 2 diabetes, and other health/cognition conditions. It is clear that the biological need for sleep varies dramatically among humans. Sleep and circadian disorders can include Familial Advanced Sleep Phase (FASP), Delayed Sleep Phase (DSP), Advanced Sleep Phase (ASP), Natural Short Sleepers (NSS) or Long Sleeping. In example, Natural Short Sleepers (NSS) have a lifelong tendency to sleep only 4 - 6 hours per night and to awaken refreshed and energetic. Natural Long Sleepers biologically require 9 - 10 hours/night to feel well rested. The 'Sleep and Circadian Disorders Study' (SACDS) at the University of California San Francisco, set out to investigate the mechanisms involved in regulating sleep duration, patterns and sleep quality regulation by identifying and characterization of individuals and families with unusual sleep and circadian rhythm behavior patterns. SACDS participants were screened with a "General Sleep Questionnaire" that inquired about multiple aspects of sleep, including habitual work-day versus non-work day sleep-wake schedules, permits calculation of subjective habitual initial sleep onset, final sleep offset, and number of awakenings. There was an additional screening process including demographic data, sleep, mood, behavioral and general medical questionnaires, plus the study consent. After the extensive screening of 117 participants, blood samples were collected from 38 individuals and of those 10 samples were chosen for whole exome sequencing analysis.

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Transcriptional signatures of sleep duration discordance in monozygotic twins

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