PNAS2014-02-24 5:18 PM

睡眠紊乱会扰乱人类转录组的昼夜调控 Mistimed sleep disrupts circadian regulation of the human transcriptome 

论文摘要 
哺乳动物转录组的昼夜调节是通过染色质结构和转录翻译过程中的关键调节符的周期性补偿来实现。这些周期性过程与转录后的修正过程共同构成了脑和外周组织中的昼夜振荡因子,它驱动了包括睡眠-觉醒周期在内的生理和行为节奏。人类睡眠通常是在体温较低和褪黑激素合成时的生物夜晚定时发生的。睡眠-觉醒定时和其他昼夜节律的不同步,如发生在轮班工作和时差时,与生理和内分泌的节律性受干扰有关。然而睡眠时间紊乱对昼夜节律分子调节因子产生的影响到什么程度仍有待证实。在此我们表明睡眠过程中被迫的非同步化和集中被驱动的昼夜节律中产生的睡眠紊乱会导致人类血液转录过程中周期性转录物从基线的6.4%减少至1.0%。受影响的转录物是基因表达的关键调节因子,包括那些与染色质修正过程(甲基化酶及乙酰基转移酶),转录过程(II型RNA聚合酶),翻译过程(核糖体蛋白质,起始和延伸因素),温度调节转录过程(冷诱导的RNA结合蛋白)和 包括CLOCK和ARNTL(BMAL1)在内的核心生物钟基因有关的调节因子。我们也评估了睡眠和昼夜节律的独立贡献,而且发现睡眠-觉醒周期尤其调节了转录和翻译的时机。研究数据显示睡眠时间紊乱影响了昼夜节律产生的核心分子过程并表明恰当按时入睡能显著提高人类转录组整体的暂时性管理。 

Abstract 
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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