Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome

Abstract

Significance Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, but the mechanisms involved remain largely unexplored. We show that one wk of insufficient sleep alters gene expression in human blood cells, reduces the amplitude of circadian rhythms in gene expression, and intensifies the effects of subsequent acute total sleep loss on gene expression. The affected genes are involved in chromatin remodeling, regulation of gene expression, and immune and stress responses. The data imply molecular mechanisms mediating the effects of sleep loss on health and highlight the interrelationships between sleep homeostasis, circadian rhythmicity, and metabolism.

Mistimed sleep disrupts circadian regulation of the human transcriptome

“…The observation that 6.4% of the blood transcriptome displayed a circadian expression profile when sleep occurred in phase with the central circadian clock agrees well with the proportions of rhythmic transcripts previously reported for other tissues (33) and is comparable with our previous estimate of 8.8% in the human blood transcriptome (21). The distinct bimodal distribution of phases, with night-peaking transcripts associated with the regulation of gene expression regulation and day-peaking transcripts associated with processes linked with immunity and inflammation (Table S2), is also in accordance with our previous analyses of the circadian human transcriptome in the absence of a sleep-wake cycle (21). Although the time courses of both night-and day-peaking genes were greatly disrupted in the current study, more of the day-peaking transcripts remained robustly rhythmic.…”

“…The (21). Thus, the sleep loss that accumulated during that protocol was 19.6 h and was associated with a reduction in circadian transcripts from 8.8% to 6.9%.…”

“…Future analyses of the current and previously published human (21,40) and animal data (30,31,41,42) may shed further light on the role of sleep and circadian rhythmicity on the regulation of the transcriptome. A first comparison of the current study of the effects of mistimed sleep and our previous study of the effects of insufficient sleep (21) indicates that several of the observed phenomena are robust. Thus, the bimodal distribution of peak activity and the processes associated with day or night peaks were very similar in the two studies.…”

“…We first determined whether the time courses of transcripts contained a significant near 24-h rhythmic (circadian) component using algorithms and statistical techniques previously described (21). The expression profiles of many transcripts appeared clearly circadian when sleep occurred in phase with the melatonin rhythm (Sleep 2) but developed a nonrhythmic profile when sleep occurred out of phase with the melatonin rhythm (Sleep 5) (e.g., RNA polymerase II subunit H, POLR2H; Fig.…”

Circadian regulation of lipid metabolism

“…Additionally, rotating shiftwork is associated with higher fasting TAG and free fatty acids, and lower HDLcholesterol (95,96) . Sleep disturbances and short-duration sleep caused by circadian misalignment might also exacerbate metabolic dysregulation and contribute to reduced circadian clock amplitude (97) . Obesity itself has been reported to associate with reduced amplitude of circadian rhythms in behaviour and clock gene expression in liver and adipose tissue of mice (98)(99)(100) , and could be related to the increased consumption of food during the inactive phase, as suggested in animals given free access to a high-fat diet (101) .…”