College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China.
National Institute of Biological Sciences, Beijing 102206, China; PTN graduate program, School of Life Sciences, Peking University, Beijing 100871, China.
Cell Metab. 2017 Jan 10;25(1):73-85. doi: 10.1016/j.cmet.2016.09.009. Epub 2016 Oct 20.
Circadian regulation is critically important in maintaining metabolic and physiological homeostasis. However, little is known about the possible influence of the clock on physiological abnormalities occurring under pathological conditions. Here, we report the discovery that hypoxia, a condition that causes catastrophic bodily damage, is gated by the circadian clock in vivo. Hypoxia signals conversely regulate the clock by slowing the circadian cycle and dampening the amplitude of oscillations in a dose-dependent manner. ChIP-seq analyses of hypoxia-inducible factor HIF1A and the core clock component BMAL1 revealed crosstalk between hypoxia and the clock at the genome level. Further, severe consequences caused by acute hypoxia, such as those that occur with heart attacks, were correlated with defects in circadian rhythms. We propose that the clock plays functions in fine-tuning hypoxic responses under pathophysiological conditions. We argue that the clock can, and likely should, be exploited therapeutically to reduce the severity of fatal hypoxia-related diseases.
昼夜节律调节对于维持代谢和生理平衡至关重要。然而，目前对于生物钟可能对病理条件下发生的生理异常产生的影响知之甚少。在这里，我们报告了一个发现，即缺氧这种会导致身体严重损伤的情况，是受生物钟调控的。相反，缺氧信号通过减缓生物钟周期和以剂量依赖的方式减弱振荡幅度来调节生物钟。对缺氧诱导因子 HIF1A 和核心生物钟成分 BMAL1 的 ChIP-seq 分析揭示了基因组水平上缺氧和生物钟之间的相互作用。此外，与心脏病发作等急性缺氧相关的严重后果与昼夜节律的缺陷有关。我们提出，生物钟在病理生理条件下精细调节缺氧反应中发挥作用。我们认为，可以而且很可能应该利用生物钟进行治疗，以减轻与致命缺氧相关疾病的严重程度。
