Diesel exhaust and house dust mite allergen lead to common changes in the airway methylome and hydroxymethylome.
Diesel exhaust and house dust mite allergen lead to common changes in the airway methylome and hydroxymethylome.
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DOI：
10.1093/eep/dvy020
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发表时间：
2018-07
影响因子：
3.8
通讯作者：
Ji H
中科院分区：
文献类型：
--
作者：
Zhang X;Chen X;Weirauch MT;Zhang X;Burleson JD;Brandt EB;Ji H
接触来自交通和室内尘螨（HDM）过敏原的柴油废气颗粒（DEP）会显著增加呼吸道疾病（包括哮喘）的风险。DEP和HDM的负面影响可能部分由表观遗传机制介导。除了作为机械屏障的功能外，气道上皮细胞为DEP和HDM暴露提供了第一道免疫防线。为了了解气道上皮细胞对这些暴露的表观遗传反应，我们将人支气管上皮细胞暴露于DEP和HDM中，并在碱基分辨率下研究全基因组5-甲基胞嘧啶（5mC）和5-羟基甲基胞嘧啶（5hmC）。我们发现暴露于DEP和HDM导致TET1和DNMT1表达升高，与5mC和5hmC变化相关。有趣的是，超过20%的CpG位点对暴露和这些位点的5mC变化都有反应，这些位点与基因表达差异呈负相关。这些5mC和5hmC的变化位于与氧化应激反应、上皮功能和免疫细胞反应相关的基因和通路中，并富集了这些通路中涉及的转录因子（tf）的结合位点。与启动子、增强子和活性转录基因体相关的组蛋白标记与暴露诱导的DNA甲基化变化有关。总的来说，我们的数据表明，暴露于DEP和HDM会改变TFs结合的调控区域的5mC和5hmC水平，这些区域与组蛋白标记协调，调节氧化应激反应、上皮功能和免疫细胞反应的基因网络。这些观察结果对介导气道上皮对DEP和HDM反应的表观遗传机制提供了新的见解。
Exposures to diesel exhaust particles (DEP) from traffic and house dust mite (HDM) allergens significantly increase risks of airway diseases, including asthma. This negative impact of DEP and HDM may in part be mediated by epigenetic mechanisms. Beyond functioning as a mechanical barrier, airway epithelial cells provide the first line of immune defense towards DEP and HDM exposures. To understand the epigenetic responses of airway epithelial cells to these exposures, we exposed human bronchial epithelial cells to DEP and HDM and studied genome-wide 5-methyl-cytosine (5mC) and 5-hydroxy-methylcytosine (5hmC) at base resolution. We found that exposures to DEP and HDM result in elevated TET1 and DNMT1 expression, associated with 5mC and 5hmC changes. Interestingly, over 20% of CpG sites are responsive to both exposures and changes in 5mC at these sites negatively correlated with gene expression differences. These 5mC and 5hmC changes are located in genes and pathways related to oxidative stress responses, epithelial function and immune cell responses and are enriched for binding sites of transcription factors (TFs) involved in these pathways. Histone marks associated with promoters, enhancers and actively transcribed gene bodies were associated with exposure-induced DNA methylation changes. Collectively, our data suggest that exposures to DEP and HDM alter 5mC and 5hmC levels at regulatory regions bound by TFs, which coordinate with histone marks to regulate gene networks of oxidative stress responses, epithelial function and immune cell responses. These observations provide novel insights into the epigenetic mechanisms that mediate the epithelial responses to DEP and HDM in airways.