Global hypomethylation in childhood asthma identified by genome‐wide DNA‐methylation sequencing preferentially affects enhancer regions

表观遗传学 DNA甲基化 差异甲基化区 生物 CpG站点 遗传学 亚硫酸氢盐测序 表观遗传学 甲基化 增强子 基因 免疫学 基因表达
作者
Loreen Thürmann,Matthias Klös,Sebastian D. Mackowiak,Matthias Bieg,Tobias Bauer,Naveed Ishaque,Marey Messingschlager,Carl Herrmann,Stefan Röder,Mario Bauer,Sascha Schäuble,Erik Faessler,Udo Hahn,Dieter Weichenhan,Oliver Mücke,Christoph Plass,Michael Borte,Erika von Mutius,Gabriele I. Stangl,Roger Lauener,Anne M. Karvonen,Amandine Divaret‐Chauveau,Josef Riedler,Joachim Heinrich,Marie Standl,Andrea von Berg,Beate Schaaf,Gunda Herberth,Michael Kabesch,Roland Eils,Saskia Trump,Irina Lehmann
出处
期刊:Allergy [Wiley]
卷期号:78 (6): 1489-1506 被引量:8
标识
DOI:10.1111/all.15658
摘要

Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.
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