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Environmental factors can cause epigenetic & microRNA(miRNA) changes that may be associated with increased susceptibility to preeclampsia(PE). DNA methylation, histone modification, and miRNA regulation orchestrate a complex epigenetic signature without altering the gene sequence, while regulating gene expression. Our objective was to investigate the relationship between first trimester epigenetic & miRNA interaction in severe PE(SPE).
Case control study of patients presenting for aneuploidy screening at 11-14 weeks gestation. In an initial study, DNA methylation was measured via Comprehensive High-throughput Arrays(CHARM) on 6 cases(SPE) & 6 controls. Infinium HumanMethylation450 was run on 12 additional SPE and 24 controls. Genome studio was used to calculate average β values which were corrected for multiplicity. TaqMan Array was used to determine miRNA & epigenetic enzyme gene expression. Only expression with a Cq ≤ 32 were included (DataAssis -corrected for false discovery rate). U6(Normfinder) was used as the reference. Post-translationally modified histones were measured by reverse-phase liquid chromatography mass spectrometry. Target scan, mirBASE & Ingenuity Pathway were used to develop an underlying mechanism for the development of SPE.
81 hypomethylated genes were associated with SPE(30-45% changes noted in the SPE vs controls in CHARM). 86 CpG islands with q-values of 0.01 were identified using the Infinium. Of the 86 sites, 54 were associated with genes(4 hyper- & 50 hypomethylated). 35 miRNAs were up regulated in SPE(p<0.05). Increased H4 acetylation was observed in SPE patients. Six epigenetic genes including HDAC5 showed significant changes in SPE(P<0.05). Figure shows a putative model of above findings.
Using a comprehensive approach incorporating assessment of epigenetics and miRNA, we discovered a novel interactive model which may account for the development of SPE. This discovery may prove to be useful in identifying first trimester markers for the prediction of SPE.