Lech Karolina, Ackermann Katrin, Revell Victoria L, Lao Oscar, Skene Debra J, Kayser Manfred
Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands EaStCHEM School of Chemistry, Biomedical Sciences Research Complex and Centre of Magnetic Resonance, University of St Andrews, St Andrews, United Kingdom.
J Biol Rhythms. 2016 Feb;31(1):68-81. doi: 10.1177/0748730415611761. Epub 2015 Nov 2.
The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings.
迄今为止，对新型生物钟调控基因（CCGs）的鉴定和研究主要在夜行性啮齿动物等模式生物中进行，而在人类中的相关信息有限。在此，我们旨在通过睡眠/睡眠剥夺（S/SD）研究和持续常规作息（CR）研究，来描述人类外周血中CCGs的每日和昼夜表达节律。在S/SD研究的12名参与者中，对9个候选CCGs（SREBF1、TRIB1、USF1、THRA1、SIRT1、STAT3、CAPRIN1、MKNK2和ROCK2）的血液表达水平进行了48小时的测量；在CR研究的12名参与者中，进行了33小时的测量。在S/SD研究和CR研究的样本中，均观察到STAT3、SREBF1、TRIB1和THRA1的表达具有统计学意义的节律，这表明它们的节律性是由内源性生物钟驱动的。MKNK2基因在S/SD研究中具有显著节律性，但在CR研究中没有，这意味着其节律性表达是由外源性因素驱动的。此外，我们在CR研究样本中证实了PER1、PER3和REV-ERBα的昼夜表达，而BMAL1和HSPA1B在CR样本中没有显著节律性；这5个基因此前在S/SD研究样本中均显示出显著表达。总体而言，我们的结果表明，人类血细胞中生物钟和选定的生物钟调控基因的节律性表达模式部分由外源性因素（睡眠和禁食状态）决定，部分由内源性昼夜节律系统决定。在选择潜在的候选标记基因以用于未来医学和法医领域的应用之前，需要了解基因表达节律的外源性和内源性调控。
