Abstract
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.
Highlights
Allergy and, allergic asthma, often starts early in life [1,2,3,4,5,6]
A much greater number of differentially expressed genes was detected in dendritic cells (DC) from allergenstimulated pups
We have found a substantially greater number of differentially expressed transcripts after allergen stimulation. 707 transcripts were differentially expressed overall in asthma-at-risk vs naive DC (FDR 0.05 and fold change 1.25 or greater), and 347 of them were present in the methylation ‘hit list’ as differentially methylated in asthma-at-risk vs naive DC. 62 of the transcripts were associated with unmethylated differentially methylated regions (DMRs) in normal naıve DC, and 101 in asthma-at-risk (25 transcripts contain both)
Summary
Allergic asthma, often starts early in life [1,2,3,4,5,6]. The onset of the disease is crucially linked to the decision-making point in the immune system, when the machinery of dendritic cells (DC) determines whether or not the protein is recognized as allergen for presentation to T-cells in a particular context [7,8,9,10] This leads to development of a Th2 milieu that later maintains the allergy process [11,12,13]. In our mouse model [14] genetically and environmentally identical neonates of asthmatic mothers develop allergy more readily compared to control counterparts coming from normal parents or asthmatic fathers This model mirrors epidemiologic studies in humans [15,16,17,18,19] and indicates nongenetic and non-environmental transmission of asthma risk from the mother. In adoptive transfer experiments [20] DCs from asthma-at-risk pups to normal pups, but not macrophages, CD4 T-cells, or DC-depleted splenocytes, caused increased susceptibility to asthma in the recipients, indicating that DCs of asthma-at-risk pups are skewed early in life to induce allergic responses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
