Epigenetic Alterations by DNA Methylation in House Dust Mite-Induced Airway Hyperresponsiveness
Epigenetic Alterations by DNA Methylation in House Dust Mite-Induced Airway Hyperresponsiveness
复制标题
屋尘螨诱导的气道高反应性中 DNA 甲基化引起的表观遗传改变。
DOI：
10.1165/rcmb.2012-0403oc
复制
发表时间：
2013-08-01
影响因子：
6.4
通讯作者：
Tang, Wan-yee
中科院分区：
文献类型：
--
作者：
Shang, Yan;Das, Sandhya;Tang, Wan-yee
哮喘是最常见的慢性肺部疾病之一，影响着全球2.35亿人，其相关发病率和死亡率在过去20年中稳步上升。暴露于环境过敏原--屋尘螨(HDM)，会导致呼吸道炎症，并伴有不同程度的呼吸道阻塞。尽管过去已经有许多实验工作使用HDM挑战模型来了解过敏性炎症和呼吸道高反应性(AHR)的机制细节，但还没有研究通过表观遗传机制介导的肺或呼吸道对急性HDM暴露的反应。6周龄雄性小鼠在第1、14和21天分别给予HDM提取物或生理盐水。小鼠暴露在HDM提取物中会引起显著的呼吸道炎症，并增加AHR。与盐水暴露(对照)小鼠相比，这些受到HDM挑战的小鼠的整体DNA甲基化也发生了变化。接下来，通过使用甲基化敏感的限制性指纹图，我们鉴定了一组与HDM诱导的AHR相关的基因，显示出异常的甲基化状态。这些候选基因分别参与cAMP信号转导(PDE4d)、Akt信号转导(AKT1 S1)、离子转运(tm6 sf1、pom121l2和slc8a3)和脂肪酸代谢(ACSL3)。在HDM暴露的小鼠中，SLC8a3和ACSL3表达下调，而PDE4d、AKT1 S1、tm6 SF1和pom121l2表达上调。因此，我们的结果表明，HDM暴露诱导了一系列异常的甲基化基因，这些基因对过敏性AHR的发展具有潜在的重要作用。
Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world, with its related morbidity and mortality increasing steadily over the last 20 years. Exposure to the environmental allergen, house dust mite (HDM), results in airway inflammation with a variable degree of airway obstruction. Although there has been much experimental work in the past using HDM challenge models to understand mechanistic details in allergic inflammation and airway hyperresponsiveness (AHR), there has been no study on reprogramming of lung or airways mediated through epigenetic mechanisms in response to an acute HDM exposure. Male mice, 6 weeks of age, were administrated HDM extracts or saline at Days 1, 14, and 21. Exposure of mice to HDM extracts caused significant airway inflammation and increased AHR. These HDM-challenged mice also exhibited a change in global DNA methylation as compared with saline-exposed (control) mice. Next, by employing methylation-sensitive restriction fingerprinting, we identified a set of genes, showing aberrant methylation status, associated with the HDM-induced AHR. These candidate genes are known to be involved in cAMP signaling (pde4 d), Akt-signaling (akt1 s1), ion transport (tm6 sf1, pom121l2, and slc8a3), and fatty acid metabolism (acsl3). Slc8a3 and acsl3 were down-regulated, whereas pde4 d, akt1 s1, tm6 sf1, and pom121l2 were up-regulated in the mice exposed to HDM. Hence, our results suggest that HDM exposure induces a series of aberrant methylated genes that are potentially important for the development of allergic AHR.