Hollis Henry C, Francis Julian N, Anafi Ron C
School of Biomedical Engineering and Health Systems, Drexel University, Philadelphia, PA, United States.
Department of Mathematics, Howard University, Washington, DC, United States.
Front Physiol. 2022 Aug 15;13:942704. doi: 10.3389/fphys.2022.942704. eCollection 2022.
Both critical illness and current care have been hypothesized to upset daily rhythms and impair molecular circadian function. However, the influence of critical illness on clock function in different tissues and on circadian output genes are unknown. Here we evaluate the effect of critical care and illness on transcription, focusing on the functional organization of the core circadian oscillator. We downloaded RNAseq count data from the Genotype-Tissue Expression (GTEx) project. Treating mechanical ventilation as a marker for intensive care, we stratified samples into acute death (AD) and intensive care (IC) groups based on the documented Hardy Death Scale. We restricted our analysis to the 25 tissues with >50 samples in each group. Using the edgeR package and controlling for collection center, gender, and age, we identified transcripts differentially expressed between the AD and IC groups. Overrepresentation and enrichment methods were used to identify gene sets modulated by intensive care across tissues. For each tissue, we then calculated the delta clock correlation distance (ΔCCD), a comparative measure of the functional organization of the core circadian oscillator, in the both the AD and IC groups. The statistical significance of the ΔCCD was assessed by permutation, modifying a pre-existing R package to control for confounding variables. Intensive care, as marked by ventilation, significantly modulated the expression of thousands of genes. Transcripts that were modulated in ≥75% of tissues were enriched for genes involved in mitochondrial energetics, cellular stress, metabolism, and notably circadian regulation. Transcripts that were more markedly affected, in ≥10 tissues, were enriched for inflammation, complement and immune pathways. Oscillator organization, as assessed by ΔCCD, was significantly reduced in the intensive care group in 11/25 tissues. Our findings support the hypothesis that patients in intensive care have impaired molecular circadian rhythms. Tissues involved in metabolism and energetics demonstrated the most marked changes in oscillator organization. In adipose tissue, there was a significant overlap between transcripts previously established to be modulated by sleep deprivation and fasting with those modulated by critical care. This work suggests that intensive care protocols that restore sleep/wake and nutritional rhythms may be of benefit.
重症疾病和当前的治疗方式都被认为会扰乱日常节律并损害分子昼夜节律功能。然而，重症疾病对不同组织中生物钟功能以及昼夜节律输出基因的影响尚不清楚。在此，我们评估重症监护和疾病对转录的影响，重点关注核心昼夜节律振荡器的功能组织。我们从基因型 - 组织表达（GTEx）项目下载了RNAseq计数数据。将机械通气作为重症监护的标志，我们根据记录的哈代死亡量表将样本分为急性死亡（AD）组和重症监护（IC）组。我们将分析限制在每组有超过50个样本的25种组织上。使用edgeR软件包并控制采集中心、性别和年龄，我们确定了AD组和IC组之间差异表达的转录本。使用过表达和富集方法来识别跨组织受重症监护调节的基因集。然后，对于每种组织，我们在AD组和IC组中计算了δ时钟相关距离（ΔCCD），这是一种衡量核心昼夜节律振荡器功能组织的比较指标。通过置换评估ΔCCD的统计学意义，修改一个现有的R软件包以控制混杂变量。以通气为标志的重症监护显著调节了数千个基因的表达。在≥75%的组织中被调节的转录本富含参与线粒体能量代谢、细胞应激、代谢以及特别是昼夜节律调节的基因。在≥10种组织中受影响更明显的转录本富含炎症、补体和免疫途径相关基因。通过ΔCCD评估的振荡器组织在11/25种组织的重症监护组中显著降低。我们的研究结果支持这样的假设，即重症监护患者的分子昼夜节律受损。参与代谢和能量代谢的组织在振荡器组织方面表现出最显著的变化。在脂肪组织中，先前确定受睡眠剥夺和禁食调节的转录本与受重症监护调节的转录本之间存在显著重叠。这项工作表明，恢复睡眠/觉醒和营养节律的重症监护方案可能有益。
