Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
PLoS One. 2013 Aug 12;8(8):e70387. doi: 10.1371/journal.pone.0070387. eCollection 2013.
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.
我们研究了出生时表观基因组广泛的甲基化异常与由于母亲哮喘而导致的新生儿树突状细胞（DC）中过敏原致敏时的基因组转录变化之间的联系。我们之前的研究表明，哮喘母亲的新生儿出生时脾脏 DC 功能偏向，即使在过敏原-naïve 幼崽中也能观察到，并且可以将过敏反应传递给正常接受者。然而，发现很少有转录或表型变化可以解释这种改变。在这里，我们提供了在过敏原致敏前后进行的全基因组 DNA 甲基化谱和 RNA 转录（微阵列）谱的深入分析。我们确定了差异甲基化和差异表达的基因座，并对关键调节序列（启动子和 CpG 岛）的甲基化状态与致敏前后各自转录物的表达进行了手动整理匹配。我们发现，与对照相比，哮喘高危新生儿的过敏原-naive DC 的转录变化最小，但甲基化变化广泛。只有在过敏原致敏时，才会发生大量转录变化，并且在存在预先存在的表观遗传改变的多个基因中发生。我们证明，母亲哮喘导致新生儿 DC 中出现高甲基化和低甲基化，并且各种基因座的这两种类型的事件与过敏原的转录反应显著重叠。途径分析表明，大约 1/2 的差异表达和差异甲基化基因直接相互作用于已知与过敏和哮喘过程相关的网络。我们得出结论，DC 中的先天性表观遗传变化与过敏原致敏时的转录反应改变和生命早期哮喘的发生密切相关。这些发现与哮喘是一种具有潜在表观遗传变化的疾病的新兴观点一致。
