BACKGROUND Humans are subjected to various environmental stressors (bacteria, viruses, pollution) throughout life. As such, an inherent relationship exists between the effect of these exposures with age. The impact of these environmental stressors can manifest through DNA methylation (DNAm). However, whether these epigenetic effects selectively target genes, pathways, and biological regulatory mechanisms remains unclear. Due to the frequency of human rhinovirus (HRV) infections throughout life (particularly in early development), we propose the use of HRV under controlled conditions can model the effect of multiple exposures to environmental stressors. METHODS We generated a prediction model by combining transcriptome and DNAm datasets from human epithelial cells after repeated HRV infections. We applied a novel experimental statistical design and method to systematically explore the multifaceted experimental space (number of infections, multiplicity of infections and duration). Our model included 35 samples, each characterized by the three parameters defining their infection status. RESULTS Trainable genes were defined by a consistent linear directionality in DNAm and gene expression changes with successive infections. We identified 77 trainable genes which could be further explored in future studies. The identified methylation sites were tracked within a pediatric cohort to determine the relative changes in candidate-trained sites with disease status and age. CONCLUSIONS Repeated viral infections induce an immune training response in bronchial epithelial cells. Training-sensitive DNAm sites indicate alternate divergent associations in asthma compared to healthy individuals. Our novel model presents a robust tool for identifying trainable genes, providing a foundation for future studies.

中文翻译：

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通过反复鼻病毒感染对人支气管上皮细胞进行表观遗传训练。


背景 人类一生都会受到各种环境压力源（细菌、病毒、污染）的影响。因此，这些暴露与年龄的影响之间存在内在的关系。这些环境压力源的影响可以通过 DNA 甲基化 （DNAm） 表现出来。然而，这些表观遗传效应是否选择性地靶向基因、通路和生物调控机制仍不清楚。由于人类鼻病毒 （HRV） 感染在一生中（尤其是在早期发育中）的频率很高，我们建议在受控条件下使用 HRV 可以模拟多次暴露于环境压力源的影响。方法 我们通过结合反复 HRV 感染后人类上皮细胞的转录组和 DNAm 数据集来生成预测模型。我们应用了一种新的实验统计设计和方法来系统地探索多方面的实验空间 （感染数量、感染的多重性和持续时间）。我们的模型包括 35 个样本，每个样本都由定义其感染状态的三个参数表征。结果 可训练基因由 DNAm 的一致线性方向性和基因表达随连续感染的变化来定义。我们确定了 77 个可训练基因，可以在未来的研究中进一步探索。在儿科队列中跟踪已鉴定的甲基化位点，以确定候选训练位点与疾病状态和年龄的相对变化。结论 反复病毒感染诱导支气管上皮细胞免疫训练反应。训练敏感的 DNAm 位点表明，与健康个体相比，哮喘存在不同的关联。 我们的新模型为识别可训练基因提供了一种强大的工具，为未来的研究奠定了基础。