Epigenomic response to albuterol treatment in asthma-relevant airway epithelial cells.
Epigenomic response to albuterol treatment in asthma-relevant airway epithelial cells.
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DOI：
10.1186/s13148-023-01571-0
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发表时间：
2023-10-03
影响因子：
5.7
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中科院分区：
文献类型：
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沙丁胺醇是用于不同人群的一线哮喘药物。虽然DNA甲基化(DNaM)是哮喘和支气管扩张剂药物反应(BDR)的表观遗传学机制，但还没有研究评估沙丁胺醇是否会导致呼吸道上皮甲基组的变化。我们的目的是描述沙丁胺醇诱导的呼吸道上皮细胞dNaM的变化，并评估潜在的功能后果以及遗传变异和哮喘相关临床变量的影响。我们遵循了一项发现和验证性研究设计，以表征沙丁胺醇在体外刺激的成对呼吸道上皮细胞培养中沙丁胺醇诱导的dNaM变化。在发现阶段，一项表观基因组范围的相关性研究使用来自波多黎各儿童(n = 97)的成对鼻上皮培养物确定了22个与重复使用沙丁胺醇治疗相关的全基因组Cpg(p <； 9 × 10-8)。沙丁胺醇主要诱导基因组中EPIC阵列捕获的CpG的低甲基化效应(低甲基化概率：76%，p值 = 3.3 × 10-5)。Cg23032799(CREB3L1)、cg00483640(MYLK4-LINC01600)和cg05673431(KSR1)上的dNaM改变在10个独立供者的鼻黏膜上皮细胞中得到验证(假发现率[FDR] <； 0.05)。对CpGcg23032799(CREB3L1)的影响在名义水平上在支气管上皮细胞中得到了跨组织验证(p = 0.030)。这三种CPG的dNaM变化受到三个独立的遗传变异的影响(fdr， <； ，0.05)。在计算机分析中发现，这些多态调控了肺和/或成纤维细胞中邻近基因的基因表达，包括KSR1和LINC01600(6.30 × 10-14 ≤ p ≤ 6.60 × 10-5)。此外，cg10290200(Flnc)和cg05673431(Ksr1)上的低甲基化与其所在基因的基因表达增加有关(fdr <； 0.05)。此外，虽然沙丁胺醇的表观遗传效应与哮喘状态、严重程度和药物使用无关，但BDR名义上与CpG cg23032799(CREB3L1)的影响有关(p = 0.004)。基因集浓缩分析表明，沙丁胺醇的表观基因组修饰可参与哮喘相关过程(如IL-2、肿瘤坏死因子-α和核因子-κB信号通路)。最后，9个差异甲基化区域与沙丁胺醇治疗相关，包括CREB3L1、MYLK4和KSR1(调整p值 <； 0.05)。这项研究揭示了沙丁胺醇诱导的粘膜纤毛上皮表观遗传修饰的证据。沙丁胺醇诱导的表观基因组反应可能通过影响与哮喘相关的生物学途径而具有潜在的临床意义。网上版载有补充材料，可在10.1186/s13148023-01571-0查阅。
Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables. We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10–8). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10–5). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10–14 ≤ p ≤ 6.60 × 10–5). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05). This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma. The online version contains supplementary material available at 10.1186/s13148-023-01571-0.
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影响因子：
10
作者：
Hancox, RJ;Stevens, DA;Taylor, DR
通讯作者：
Taylor, DR
影响因子：
5.7
作者：
Campagna MP;Xavier A;Lechner-Scott J;Maltby V;Scott RJ;Butzkueven H;Jokubaitis VG;Lea RA
通讯作者：
Lea RA
影响因子：
14.2
作者：
Gao, Li;Grant, Audrey V.;Barnes, Kathleen C.
通讯作者：
Barnes, Kathleen C.
哮喘的拉丁裔儿童和青少年的肺功能全基因组协会研究。
影响因子：
5.7
作者：
Herrera-Luis E;Li A;Mak ACY;Perez-Garcia J;Elhawary JR;Oh SS;Hu D;Eng C;Keys KL;Huntsman S;Beckman KB;Borrell LN;Rodriguez-Santana J;Burchard EG;Pino-Yanes M
通讯作者：
Pino-Yanes M
DOI：
10.1007/978-1-4939-7896-0_30
发表时间：
2018-01-01
期刊：
TYPE 2 IMMUNITY: METHODS AND PROTOCOLS
影响因子：
--
作者：
Everman, Jamie L.;Rios, Cydney;Seibold, Max A.
通讯作者：
Seibold, Max A.