Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 18, 2013 (received for review August 29, 2013)
Disruption of the timing of the sleep–wake cycle and circadian rhythms, such as occurs during jet lag and shift work, leads to disordered physiological rhythms, but to what extent the molecular elements of circadian rhythm generation are affected is not known. Here, we show that delaying sleep by 4 h for 3 consecutive days leads to a sixfold reduction of circadian transcripts in the human blood transcriptome to just 1%, whereas, at the same time, the centrally driven circadian rhythm of melatonin is not affected. Genes and processes affected included those at the core of circadian rhythm generation and gene expression. The data have implications for understanding the negative health outcomes of disruption of the sleep–wake cycle.
Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic processes, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep–wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized. Desynchrony of sleep–wake timing and other circadian rhythms, such as occurs in shift work and jet lag, is associated with disruption of rhythmicity in physiology and endocrinology. However, to what extent mistimed sleep affects the molecular regulators of circadian rhythmicity remains to be established. Here, we show that mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony of sleep and centrally driven circadian rhythms. Transcripts affected are key regulators of gene expression, including those associated with chromatin modification (methylases and acetylases), transcription (RNA polymerase II), translation (ribosomal proteins, initiation, and elongation factors), temperature-regulated transcription (cold inducible RNA-binding proteins), and core clock genes including CLOCK and ARNTL (BMAL1). We also estimated the separate contribution of sleep and circadian rhythmicity and found that the sleep–wake cycle coordinates the timing of transcription and translation in particular. The data show that mistimed sleep affects molecular processes at the core of circadian rhythm generation and imply that appropriate timing of sleep contributes significantly to the overall temporal organization of the human transcriptome.
↵1S.N.A., E.E.L., and C.S.M.-L. 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; E.E.L., C.S.M.-L., D.R.v.d.V., G.B., A.S.L., N.S., A.S., and R.K. performed research; S.N.A., E.E.L., C.S.M.-L., G.B., and R.K. analyzed data; and S.N.A., E.E.L., C.S.M.-L., D.R.v.d.V., 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. GSE48113).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1316335111/-/DCSupplemental.
Freely available online through the PNAS open access option.
