Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved January 23, 2013 (received for review October 3, 2012)
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.
Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, including obesity, cardiovascular disease, and cognitive impairment, but the mechanisms involved remain largely unexplored. Twenty-six participants were exposed to 1 wk of insufficient sleep (sleep-restriction condition 5.70 h, SEM = 0.03 sleep per 24 h) and 1 wk of sufficient sleep (control condition 8.50 h sleep, SEM = 0.11). Immediately following each condition, 10 whole-blood RNA samples were collected from each participant, while controlling for the effects of light, activity, and food, during a period of total sleep deprivation. Transcriptome analysis revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms (PER1, PER2, PER3, CRY2, CLOCK, NR1D1, NR1D2, RORA, DEC1, CSNK1E), sleep homeostasis (IL6, STAT3, KCNV2, CAMK2D), oxidative stress (PRDX2, PRDX5), and metabolism (SLC2A3, SLC2A5, GHRL, ABCA1). Biological processes affected included chromatin modification, gene-expression regulation, macromolecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation. The identified biological processes may be involved with the negative effects of sleep loss on health, and highlight the interrelatedness of sleep homeostasis, circadian rhythmicity, and metabolism.
↵1C.S.M.-L., S.N.A., G.B., C.P.S., and D.-J.D. contributed equally to this work.
Author contributions: S.N.A., E.E.L., M.v.S., C.P.S., and D.-J.D. designed research; C.S.M.-L., G.B., E.E.L., A.S., R.K., J.C.Y.L., and N.S. performed research; C.S.M.-L., G.B., E.E.L., A.S., and R.K. analyzed data; and C.S.M.-L., S.N.A., E.E.L., M.v.S., C.P.S., and D.-J.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE39445). Custom microarray design deposited at GEO (accession no. GPL15331).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1217154110/-/DCSupplemental.
Freely available online through the PNAS open access option.
