Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk.
Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk.
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DOI：
10.1371/journal.pone.0070387
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fedulov AV
中科院分区：
文献类型：
--
作者：
Mikhaylova L;Zhang Y;Kobzik L;Fedulov AV
我们研究了出生时表观基因组全甲基化异常与由母亲哮喘引起的新生儿树突状细胞（DC）过敏原致敏时基因组转录变化之间的联系。我们之前证明，哮喘母亲的新生儿出生时脾脏dc功能偏斜，即使在allergen-naïve幼崽中也可以看到，并且可以向正常受体传递过敏反应。然而，很少甚至没有发现转录或表型变化来解释这种改变。在这里，我们深入分析了过敏原致敏前后的全基因组DNA甲基化谱和RNA转录（微阵列）谱。我们确定了差异甲基化和差异表达的位点，并对关键调控序列（启动子和CpG岛）在致敏前后的甲基化状态与各自转录本的表达进行了人工匹配。我们发现，与对照组相比，来自哮喘高危新生儿的无过敏原dc的转录变化最小，但甲基化变化广泛。实质性的转录变化只有在过敏原致敏时才会变得明显，当它发生在多个基因中并伴有预先存在的表观遗传改变时。我们证明，母亲哮喘导致新生儿dc的高甲基化和低甲基化，并且在不同的位点上，这两种类型的事件与对过敏原的转录反应显著重叠。通路分析表明，大约1/2的差异表达和差异甲基化基因在过敏和哮喘过程的已知网络中直接相互作用。我们得出结论，dc的先天性表观遗传变化与对过敏原的转录反应改变和早期哮喘起源密切相关。这些发现与哮喘是一种具有潜在表观遗传变化的疾病这一新兴范式相一致。
We investigated the link between epigenome-wide methylation aberrations at birth and genomic transcriptional changes upon allergen sensitization that occur in the neonatal dendritic cells (DC) due to maternal asthma. We previously demonstrated that neonates of asthmatic mothers are born with a functional skew in splenic DCs that can be seen even in allergen-naïve pups and can convey allergy responses to normal recipients. However, minimal-to-no transcriptional or phenotypic changes were found to explain this alteration. Here we provide in-depth analysis of genome-wide DNA methylation profiles and RNA transcriptional (microarray) profiles before and after allergen sensitization. We identified differentially methylated and differentially expressed loci and performed manually-curated matching of methylation status of the key regulatory sequences (promoters and CpG islands) to expression of their respective transcripts before and after sensitization. We found that while allergen-naive DCs from asthma-at-risk neonates have minimal transcriptional change compared to controls, the methylation changes are extensive. The substantial transcriptional change only becomes evident upon allergen sensitization, when it occurs in multiple genes with the pre-existing epigenetic alterations. We demonstrate that maternal asthma leads to both hyper- and hypomethylation in neonatal DCs, and that both types of events at various loci significantly overlap with transcriptional responses to allergen. Pathway analysis indicates that approximately 1/2 of differentially expressed and differentially methylated genes directly interact in known networks involved in allergy and asthma processes. We conclude that congenital epigenetic changes in DCs are strongly linked to altered transcriptional responses to allergen and to early-life asthma origin. The findings are consistent with the emerging paradigm that asthma is a disease with underlying epigenetic changes.
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作者：
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通讯作者：
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DOI：
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