Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma
Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma
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DOI：
10.4161/epi.33066
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发表时间：
2014-09-01
期刊：
影响因子：
3.7
通讯作者：
Baines, Katherine J.
中科院分区：
文献类型：
--
作者：
Gunawardhana, Lakshitha P.;Gibson, Peter G.;Baines, Katherine J.
环境暴露引起的表观遗传学改变，包括DNA甲基化，可能是哮喘异质性炎症反应的原因之一。在这里，我们研究了与哮喘炎症表型相关的纯化血液单核细胞DNA甲基化的改变。从嗜酸性粒细胞性哮喘（EA; n = 21）、少粒细胞性哮喘（PGA; n = 22）、嗜酸性粒细胞性哮喘（NA; n = 9）和健康对照（n = 10）的成人中收集外周血。使用聚蔗糖密度梯度和免疫磁性细胞分离法分离血液单核细胞。将亚硫酸氢盐转化的基因组DNA与Illumina Infinium Methylation 27阵列杂交，并使用R/Bioconductor软件包分析差异甲基化;使用STRING数据库识别基因相互作用网络。与健康对照组相比，在EA（n = 413），PGA（n = 495）和NA（n = 89）中鉴定出差异甲基化的CpG位点。我们发现，223，237和72个位点显着高甲基化的EA，PGA和NA，分别。9个基因在所有三种表型中是共同的，并且在哮喘中显示出甲基化增加。EA中存在3个通路网络，分别涉及嘌呤代谢、钙信号和ECM-受体相互作用。在PGA中，确定了两个网络，涉及神经活性配体-受体相互作用和泛素介导的蛋白水解。在NA中，确定了一个涉及sFRP 1作为关键节点的网络，超过了Wnt信号通路。我们已经确定了与哮喘炎症表型相关的DNA甲基化的特征性改变，并可能有助于疾病机制。这种基于网络的表征可能有助于开发哮喘的表观遗传生物标志物和治疗靶点。
Epigenetic changes including DNA methylation caused by environmental exposures may contribute to the heterogeneous inflammatory response in asthma. Here we investigate alterations in DNA methylation of purified blood monocytes that are associated with inflammatory phenotypes of asthma. Peripheral blood was collected from adults with eosinophilic asthma (EA; n = 21), paucigranulocytic asthma (PGA; n = 22), neutrophilic asthma (NA; n = 9), and healthy controls (n = 10). Blood monocytes were isolated using ficoll density gradient and immuno-magnetic cell separation. Bisulfite converted genomic DNA was hybridized to Illumina Infinium Methylation27 arrays and analyzed for differential methylation using R/Bioconductor packages; networks of gene interactions were identified using the STRING database. Compared with healthy controls, differentially methylated CpG loci were identified in EA (n = 413), PGA (n = 495), and NA (n = 89). We found that 223, 237, and 72 loci were significantly hypermethylated in EA, PGA, and NA, respectively. Nine genes were common to all three phenotypes and showed increased methylation in asthma. Three pathway networks were identified in EA, involved in purine metabolism, calcium signaling, and ECM-receptor interaction. In PGA, two networks were identified, involved in neuroactive ligand-receptor interaction and ubiquitin mediated proteolysis. In NA, one network was identified involving sFRP1 as a key node, over representing the Wnt signaling pathway. We have identified characteristic alterations in DNA methylation that are associated with inflammatory phenotypes of asthma and may contribute to the disease mechanisms. This network-based characterization may help in the development of epigenetic biomarkers and therapeutic targets for asthma.