Multi-tissue transcriptional changes and core circadian clock disruption following intensive care.
Multi-tissue transcriptional changes and core circadian clock disruption following intensive care.
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重症监护后多组织转录变化和核心生物钟中断。
DOI：
10.3389/fphys.2022.942704
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发表时间：
2022
影响因子：
4
通讯作者：
Anafi, Ron C.
中科院分区：
文献类型：
--
作者：
Hollis, Henry C.;Francis, Julian N.;Anafi, Ron C.
关键词：
目的：危重疾病和目前的护理都被认为会扰乱日常节律，损害分子的昼夜节律功能。然而，危重疾病对不同组织的时钟功能和昼夜节律输出基因的影响尚不清楚。在这里，我们评估危重护理和疾病对转录的影响，重点是核心昼夜节律振荡器的功能组织。方法：我们从基因类型-组织表达(GTEx)项目下载RNAseq计数数据。将机械通气作为重症监护的标志，我们根据文献记载的Hardy死亡分级将样本分成急性死亡(AD)组和重症监护(IC)组。我们将我们的分析限制在25个组织中，每组50个样本。使用Edger软件包，并对照收集中心、性别和年龄，我们鉴定了AD组和IC组之间差异表达的转录本。过度表达和富集法被用来识别跨组织的重症监护调节的基因集。然后，对于每个组织，我们计算了AD组和IC组的增量时钟相关距离(ΔCcd)，这是对核心昼夜节律振荡器功能组织的比较测量。通过排列、修改已有的R包以控制混杂变量来评估ΔCCD值的统计学意义。结果：以换气为标志的重症监护显著调节了数千个基因的表达。在≥中调节的转录本75%的组织富含涉及线粒体能量学、细胞应激、新陈代谢，特别是昼夜节律的基因。在≥10组织中，受影响更明显的转录本在炎症、补体和免疫途径方面得到了丰富。根据Δccd评估，重症监护组中有11/25的组织振荡器组织显著减少。结论：我们的发现支持重症监护患者分子昼夜节律受损的假设。参与新陈代谢和能量学的组织在振荡器组织中表现出最显著的变化。在脂肪组织中，先前被确定为受睡眠剥夺和禁食调节的转录本与那些由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/清醒和营养节律的重症监护方案可能是有益的。
Objective: 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. Methods: 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. Results: 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. Conclusion: 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.
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DOI：
10.1164/ajrccm.163.2.9912128
发表时间：
2001-02-01
影响因子：
24.7
作者：
Freedman, NS;Gazendam, J;Schwab, RJ
通讯作者：
Schwab, RJ
DOI：
10.1111/febs.15360
发表时间：
2021-01
期刊：
The FEBS journal
影响因子：
--
作者：
Cal-Kayitmazbatir S;Kulkoyluoglu-Cotul E;Growe J;Selby CP;Rhoades SD;Malik D;Oner H;Asimgil H;Francey LJ;Sancar A;Kruger WD;Hogenesch JB;Weljie A;Anafi RC;Kavakli IH
通讯作者：
Kavakli IH
影响因子：
3.1
作者：
Diaz, Elena;Diaz, Irene;Perez, Silvia
通讯作者：
Perez, Silvia
影响因子：
3.5
作者：
Haspel J;Kim M;Zee P;Schwarzmeier T;Montagnese S;Panda S;Albani A;Merrow M
通讯作者：
Merrow M
影响因子：
9.6
作者：
Gazendam, Joost A. C.;Van Dongen, Hans P. A.;Schwab, Richard J.
通讯作者：
Schwab, Richard J.