Department of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, ul. Wielicka 265, 30-663 Krakow, Poland.
Department of Pediatric Research, University of Oslo and Oslo University Hospital, Norway.
Free Radic Biol Med. 2018 Jun;121:51-56. doi: 10.1016/j.freeradbiomed.2018.04.566. Epub 2018 Apr 23.
Supplemental oxygen exposure is a risk factor for the development of bronchopulmonary dysplasia (BPD). Reactive oxygen species may damage lung tissue, but hyperoxia also has the potential to alter genome activity via changes in DNA methylation. Understanding the epigenetic potential of hyperoxia would enable further improvement of the therapeutic strategies for BPD. Here we aimed to identify hyperoxia-related alterations in DNA methylation, which could affect the activity of crucial genetic pathways involved in the development of hyperoxic lung injury. Newborn mice (n = 24) were randomized to hyperoxia (85% O) or normoxia groups for 14 days, followed by normoxia for the subsequent 14 days. The mice were sacrificed on day 28, and lung tissue was analyzed using microarrays developed for the assessment of genome methylation and expression profiles. The mean DNA methylation level was higher in the hyperoxia group than the normoxia group. The analysis of specific DNA fragments revealed hypermethylation of > 1000 gene promoters in the hyperoxia group, confirming the presence of the DNA-hypermethylation effect of hyperoxia. Further analysis showed significant enrichment of the TGF-β signaling pathway (p = 0.0013). The hypermethylated genes included Tgfbr1, Crebbp, and Creb1, which play central roles in the TGF-β signaling pathway and cell cycle regulation. Genome expression analysis revealed in the hyperoxia group complementary downregulation of genes that are crucial for cell cycle regulation (Crebbp, Smad2, and Smad3). These results suggest the involvement of the methylation of TGF-β pathway genes in lung tissue reaction to hyperoxia. The data also suggest that hyperoxia may be a programming factor in newborn mice.
补充氧气暴露是支气管肺发育不良（BPD）发展的一个风险因素。活性氧可能会损害肺组织，但高氧也有可能通过 DNA 甲基化的改变来改变基因组活性。了解高氧的表观遗传潜力将能够进一步改进 BPD 的治疗策略。在这里，我们旨在确定与高氧相关的 DNA 甲基化改变，这些改变可能会影响参与高氧性肺损伤发展的关键遗传途径的活性。将新生小鼠（n=24）随机分为高氧（85% O）或常氧组，持续 14 天，随后再常氧 14 天。在第 28 天处死小鼠，使用评估基因组甲基化和表达谱的微阵列分析肺组织。高氧组的平均 DNA 甲基化水平高于常氧组。对特定 DNA 片段的分析表明，高氧组有超过 1000 个基因启动子发生了高甲基化，证实了高氧的 DNA 高甲基化效应的存在。进一步的分析表明 TGF-β 信号通路显著富集（p=0.0013）。高甲基化的基因包括在 TGF-β 信号通路和细胞周期调节中起核心作用的 Tgfbr1、Crebbp 和 Creb1。在高氧组中，细胞周期调节的关键基因 Crebbp、Smad2 和 Smad3 表达下调。这些结果表明，TGF-β 通路基因的甲基化参与了肺组织对高氧的反应。数据还表明，高氧可能是新生小鼠的一种编程因素。
