Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution.
Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution.
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DOI：
10.1016/j.jaci.2015.10.021
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Ji H
中科院分区：
文献类型：
--
作者：
Somineni HK;Zhang X;Biagini Myers JM;Kovacic MB;Ulm A;Jurcak N;Ryan PH;Khurana Hershey GK;Ji H
哮喘是一种受遗传和环境影响的复杂疾病。最近的发现将T细胞中异常的DNA甲基化与哮喘联系在一起；然而，呼吸道上皮细胞中潜在的甲基化异常尚不清楚。对哮喘小鼠模型的研究发现，肺中5-羟甲基胞嘧啶(5-HMC)和TET1的表达水平较高。已知Tet蛋白通过将5-MC修饰为5-羟甲基胞嘧啶(5-HMC)来催化甲基化。研究了TET1甲基化与哮喘和交通相关空气污染之间的关系。用Illumina 450K阵列检测了12名患有哮喘的非裔美国儿童及其非哮喘兄弟姐妹鼻腔呼吸道上皮细胞DNA的Tet1甲基化水平。另外35对兄弟姐妹中的感兴趣区域通过基因座特异性焦磷酸测序得到验证，并在一个独立的群体中复制(N=186)。使用土地利用回归模型估计参与者早期生活和当前家庭住址的交通相关空气污染(TRAP)暴露情况。唾液、外周血单核细胞和人支气管上皮细胞(HBEC)的甲基化研究支持了我们的发现。TET1启动子(Cg23602092)上单个CpG位点的甲基化缺失和全局5hmC的增加与哮喘显著相关。相比之下，参与者目前家中的TRAP暴露显著增加了同一部位的甲基化。不同组织样本类型的模式是一致的。HBEC中5-氮杂-2‘-脱氧胞苷和柴油机尾气颗粒物暴露与TET1甲基化、表达和全球5-HMC的改变有关。我们的发现提示TET1甲基化可能在哮喘和对TRAP的反应中起作用。Tet1 DNA甲基化可能是哮喘和暴露相关哮喘加重风险较高的生物标志物。
Asthma is a complex disorder influenced by genetics and the environment. Recent findings have linked abnormal DNA methylation in T cells with asthma; however, the potential dysregulation of methylation in airway epithelial cells is unknown. Studies of mouse models of asthma have observed greater levels of 5-hydoxymethylcytosine (5-hmC) and TET1 expression in lungs. TET proteins are known to catalyze methylation through modification of 5-mC to 5-hydroxymethylcytosine (5-hmC). Associations between TET1 methylation and asthma and traffic-related air pollution were examined. TET1 methylation levels from DNA derived from nasal airway epithelial cells collected from 12 African-American children with physician-diagnosed asthma and their non-asthmatic siblings were measured using Illumina 450K arrays. Regions of interest were verified by locus-specific pyrosequencing in 35 additional sibling pairs and replicated in an independent population (N=186). Exposure to traffic-related air pollution (TRAP) at participants’ early life and current home addresses was estimated using a land-use regression model. Methylation studies in saliva, PBMCs, and human bronchial epithelial cells (HBEC) were done to support our findings. Loss of methylation at a single CpG site in the TET1 promoter (cg23602092) and increased global 5hmC was significantly associated with asthma. In contrast, TRAP exposure at participants’ current homes significantly increased methylation at the same site. Patterns were consistent across tissue sample types. 5-aza-2'-deoxycytidine and diesel exhaust particle exposure in HBEC was associated with altered TET1 methylation, expression and global 5-hmC. Our findings suggest a possible role of TET1 methylation in asthma and response to TRAP. TET1 DNA methylation might serve as a biomarker for asthma and higher risk of exposure-related asthma exacerbations.