Mistimed sleep disrupts circadian regulation of the human transcriptome

Jan 23, 2014Proceedings of the National Academy of Sciences of the United States of America

Sleeping at the Wrong Time Disrupts the Body’s Daily Gene Activity Cycle

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Abstract

Mistimed sleep reduces rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony.

Circadian rhythms in physiology and behavior are driven by rhythmic processes in the brain and peripheral tissues.
Disruption of sleep timing, as seen in shift work and jet lag, is linked to a loss of rhythmicity in physiological functions.
Key regulators of gene expression affected by mistimed sleep include proteins involved in chromatin modification, transcription, and translation.
The sleep-wake cycle plays a crucial role in coordinating the timing of transcription and translation.
Mistimed sleep may significantly impact the molecular mechanisms that generate circadian rhythms.

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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.

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Mistimed sleep disrupts circadian regulation of the human transcriptome

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