DNA methylation signatures in airway cells from adult children of asthmatic mothers reflect subtypes of severe asthma.
DNA methylation signatures in airway cells from adult children of asthmatic mothers reflect subtypes of severe asthma.
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DOI：
10.1073/pnas.2116467119
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发表时间：
2022-06-14
影响因子：
11.1
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中科院分区：
文献类型：
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母亲哮喘是儿童期发作哮喘最常见的危险因素之一。然而，其潜在机制尚不清楚。我们确定了哮喘成人支气管上皮细胞中的DNA甲基化特征，这些特征对那些母亲患有哮喘的人是特异性的。这些母亲哮喘相关的甲基化特征与不同的基因调控途径和临床特征相关。16个通路中的基因区分了患有和不患有母亲哮喘的病例，并表明哮喘母亲的哮喘儿童的T细胞信号传导和对病毒和细菌病原体的反应受损。我们的研究结果表明，哮喘母亲怀孕期间的产前环境改变了表观遗传介导的发育程序，这些程序可能通过不同的基因调控途径导致其子女发生严重哮喘。母亲哮喘（MA）是儿童哮喘最一致的危险因素之一。这一观察结果的可能机制是子宫内的表观遗传修饰，对哮喘母亲的儿童的发育程序有持久的影响。为了验证这一假设，我们对42名非哮喘对照和88名哮喘患者（包括56名无MA（NMA）和32名MA患者）的原代支气管上皮细胞（BEC）中的398，186个单个CpG位点进行了差异DNA甲基化分析。我们使用加权基因共表达网络分析（WGCNA）的69和554差异甲基化的CpG（DMC），分别是特定的NMA和MA的情况下，与对照组相比。WGCNA将66个NMA-DMC和203个MA-DMC分别分为两个和五个甲基化模块。一个MA相关模块（绿松石）的特征向量与BEC中表达的85个基因唯一相关，并富集了36条途径，其中16条使用机器学习区分NMA和MA。与NMA病例相比，MA中所有16条通路的基因均减少（P = 7.1 × 10−3），这一发现在一个独立队列的鼻上皮细胞中重复（P = 0.02）。这些途径的功能解释表明受损的T细胞信号传导和对病毒和细菌病原体的反应。MA相关的青绿色模块特征向量还与严重哮喘的临床特征相关，并反映了2型（T2）-低哮喘（即，低血清总免疫球蛋白E、呼出的一氧化氮分数和嗜酸性粒细胞增多）。总的来说，这些数据表明MA改变了导致成人严重哮喘不同亚型的多种表观遗传介导途径，包括难以治疗的T2低哮喘。
Maternal asthma is one of the most replicated risk factors for childhood-onset asthma. However, the underlying mechanisms are unknown. We identified DNA methylation signatures in bronchial epithelial cells from adults with asthma that were specific to those with a mother with asthma. These maternal asthma-associated methylation signatures were correlated with distinct gene regulatory pathways and clinical features. Genes in 16 pathways discriminated cases with and without maternal asthma and suggested impaired T cell signaling and responses to viral and bacterial pathogens in asthmatic children of an asthmatic mother. Our findings suggest that the prenatal environment in pregnancies of mothers with asthma alters epigenetically mediated developmental programs that may lead to severe asthma in their children through diverse gene regulatory pathways. Maternal asthma (MA) is among the most consistent risk factors for asthma in children. Possible mechanisms for this observation are epigenetic modifications in utero that have lasting effects on developmental programs in children of mothers with asthma. To test this hypothesis, we performed differential DNA methylation analyses of 398,186 individual CpG sites in primary bronchial epithelial cells (BECs) from 42 nonasthma controls and 88 asthma cases, including 56 without MA (NMA) and 32 with MA. We used weighted gene coexpression network analysis (WGCNA) of 69 and 554 differentially methylated CpGs (DMCs) that were specific to NMA and MA cases, respectively, compared with controls. WGCNA grouped 66 NMA-DMCs and 203 MA-DMCs into two and five comethylation modules, respectively. The eigenvector of one MA-associated module (turquoise) was uniquely correlated with 85 genes expressed in BECs and enriched for 36 pathways, 16 of which discriminated between NMA and MA using machine learning. Genes in all 16 pathways were decreased in MA compared with NMA cases (P = 7.1 × 10−3), a finding that replicated in nasal epithelial cells from an independent cohort (P = 0.02). Functional interpretation of these pathways suggested impaired T cell signaling and responses to viral and bacterial pathogens. The MA-associated turquoise module eigenvector was additionally correlated with clinical features of severe asthma and reflective of type 2 (T2)-low asthma (i.e., low total serum immunoglobulin E, fractional exhaled nitric oxide, and eosinophilia). Overall, these data suggest that MA alters diverse epigenetically mediated pathways that lead to distinct subtypes of severe asthma in adults, including hard-to-treat T2-low asthma.
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