顺式和反式eQTM分析揭示气道上皮中特应性哮喘的新表观遗传学和转录组免疫标志物
2023/06/25
摘要
背景：EQTM（表达定量性状甲基化）分析揭示了DNA甲基化标记与基因表达之间的关系。大多数复杂疾病的eQTM分析都集中在顺式eQTM对（1Mb以内）上。
目的：本研究旨在鉴定顺式和反式甲基化标记物与特应性哮喘和非特应性支气管哮喘青年气道上皮基因表达相关。
方法：本研究对158名患有特应性哮喘的波多黎各青年和100名没有特应性反应或哮喘的对照受试者的鼻（气道）上皮样本进行了顺式和反式eQTM分析。之后，本研究尝试在两项儿童研究的鼻上皮样本中复制上述发现，同时检验本研究在鼻上皮中的结果是否与波多黎各受试者白细胞eQTM分析的结果一致。
结果：本研究共鉴定出9108对顺式eQTM和2131500对反式eQTM。转录因子和miRNA靶基因的反式关联显著富集。此外，显著的CpG在特应性哮喘中被差异性甲基化，并且显著的基因富集了特应性支气管哮喘中差异表达的基因。在波多黎各青年中发现的50.7%至62.6%的顺式和反式eQTM对在FDR-P<0.1的两个较小的队列中被复制。反式eQTM分析中的复制基因包括生物学上合理的哮喘易感性基因（例如HDC、NLRP3、ITGAE、CDH26和CST1），并且在免疫途径中富集。
结论：研究气道上皮基因表达的顺式和反式表观遗传学调控可以确定儿童哮喘的潜在因果和调控途径或网络。反式eQTM-CpGs可能通过对转录因子和miRNA靶基因的影响来调节气道上皮中的基因表达。
Cis- and trans-eQTM analysis reveals novel epigenetic and transcriptomic immune markers of atopic asthma in airway epithelium.
Kim S, Xu Z, Forno E, Qin Y, Park HJ, Yue M, Yan Q, Manni M, Acosta-Pérez E, Canino G, Chen W, Celedón JC.
Abstract
BACKGROUND:EQTM (expression quantitative trait methylation) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 Mb).
OBJECTIVE:To identify cis- and trans- methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma.
METHODS:We conducted both cis- and trans-eQTM analyses in nasal (airway) epithelial samples from 158 Puerto Rican youth with atopic asthma and 100 control subjects without atopy or asthma. We then attempted to replicate our findings in nasal epithelial samples from two studies of children, while also examining whether our results in nasal epithelium overlap with those from an eQTM analysis in white blood cells from the Puerto Rican subjects.
RESULTS:We identified 9,108 cis-eQTM pairs and 2,131,500 trans-eQTM pairs. Trans-associations were significantly enriched for transcription factor- and miRNA-target genes. Further, significant CpGs were differentially methylated in atopic asthma and significant genes were enriched for genes differentially expressed in atopic asthma. 50.7% to 62.6% of cis- and trans-eQTM pairs identified in Puerto Rican youth were replicated in two smaller cohorts at FDR-P <0.1. Replicated genes in the trans-eQTM analysis included biologically plausible asthma-susceptibility genes (e.g., HDC, NLRP3, ITGAE, CDH26, and CST1) and are enriched in immune pathways.
CONCLUSIONS:Studying both cis- and trans-epigenetic regulation of airway epithelial gene expression can identify potential causal and regulatory pathways or networks for childhood asthma. Trans-eQTM CpGs may regulate gene expression in airway epithelium through effects on transcription factor- and miRNA-target genes.
背景：EQTM（表达定量性状甲基化）分析揭示了DNA甲基化标记与基因表达之间的关系。大多数复杂疾病的eQTM分析都集中在顺式eQTM对（1Mb以内）上。
目的：本研究旨在鉴定顺式和反式甲基化标记物与特应性哮喘和非特应性支气管哮喘青年气道上皮基因表达相关。
方法：本研究对158名患有特应性哮喘的波多黎各青年和100名没有特应性反应或哮喘的对照受试者的鼻（气道）上皮样本进行了顺式和反式eQTM分析。之后，本研究尝试在两项儿童研究的鼻上皮样本中复制上述发现，同时检验本研究在鼻上皮中的结果是否与波多黎各受试者白细胞eQTM分析的结果一致。
结果：本研究共鉴定出9108对顺式eQTM和2131500对反式eQTM。转录因子和miRNA靶基因的反式关联显著富集。此外，显著的CpG在特应性哮喘中被差异性甲基化，并且显著的基因富集了特应性支气管哮喘中差异表达的基因。在波多黎各青年中发现的50.7%至62.6%的顺式和反式eQTM对在FDR-P<0.1的两个较小的队列中被复制。反式eQTM分析中的复制基因包括生物学上合理的哮喘易感性基因（例如HDC、NLRP3、ITGAE、CDH26和CST1），并且在免疫途径中富集。
结论：研究气道上皮基因表达的顺式和反式表观遗传学调控可以确定儿童哮喘的潜在因果和调控途径或网络。反式eQTM-CpGs可能通过对转录因子和miRNA靶基因的影响来调节气道上皮中的基因表达。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2023 Jun 2:S0091-6749(23)00713-3. doi: 10.1016/j.jaci.2023.05.018.)
(J Allergy Clin Immunol. 2023 Jun 2:S0091-6749(23)00713-3. doi: 10.1016/j.jaci.2023.05.018.)
Cis- and trans-eQTM analysis reveals novel epigenetic and transcriptomic immune markers of atopic asthma in airway epithelium.
Kim S, Xu Z, Forno E, Qin Y, Park HJ, Yue M, Yan Q, Manni M, Acosta-Pérez E, Canino G, Chen W, Celedón JC.
Abstract
BACKGROUND:EQTM (expression quantitative trait methylation) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 Mb).
OBJECTIVE:To identify cis- and trans- methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma.
METHODS:We conducted both cis- and trans-eQTM analyses in nasal (airway) epithelial samples from 158 Puerto Rican youth with atopic asthma and 100 control subjects without atopy or asthma. We then attempted to replicate our findings in nasal epithelial samples from two studies of children, while also examining whether our results in nasal epithelium overlap with those from an eQTM analysis in white blood cells from the Puerto Rican subjects.
RESULTS:We identified 9,108 cis-eQTM pairs and 2,131,500 trans-eQTM pairs. Trans-associations were significantly enriched for transcription factor- and miRNA-target genes. Further, significant CpGs were differentially methylated in atopic asthma and significant genes were enriched for genes differentially expressed in atopic asthma. 50.7% to 62.6% of cis- and trans-eQTM pairs identified in Puerto Rican youth were replicated in two smaller cohorts at FDR-P <0.1. Replicated genes in the trans-eQTM analysis included biologically plausible asthma-susceptibility genes (e.g., HDC, NLRP3, ITGAE, CDH26, and CST1) and are enriched in immune pathways.
CONCLUSIONS:Studying both cis- and trans-epigenetic regulation of airway epithelial gene expression can identify potential causal and regulatory pathways or networks for childhood asthma. Trans-eQTM CpGs may regulate gene expression in airway epithelium through effects on transcription factor- and miRNA-target genes.
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LPS结合蛋白和激活信号在儿童哮喘发作期上调
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人类遗传学影响下的与吸入皮质类固醇治疗后哮喘恶化相关的微生物组组分研究
