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Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium.

ABSTRACT: Asthma is a chronic inflammatory disease of the airways driven by complex genetic-environmental interactions. Epigenomic mechanisms including histone modifications and DNA methylation are altered in key cell types of asthma. However, genome-wide studies of histone modifications in the airway epithelium of asthmatics have yet to be undertaken. We undertook genome-wide profiling of an enhancer (regulatory domain)-associated histone modification H3K27ac in bronchial epithelial cells (BECs) from asthmatic and healthy control individuals. We identified 49,903 (P<0.05) regions exhibiting differential H3K27ac enrichment in asthma and found they clustered predominately at genes associated with Th2-high asthma (e.g. CLCA1) and epithelial processes (e.g. EMT). We determined asthma had a dramatic influence on the enhancer landscape of BECs and identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (e.g. TP63) and enzymes involved in lipid metabolism (e.g. NOX4). We integrated published protein expression, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (e.g. TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, using a CRISPR-based approach to recapitulate the H3K27ac landscape of asthma in vitro, we provide proof of principal that asthma-associated gene expression (e.g. SERPINB2) is driven in part by aberrant histone acetylation. This report identifies the influence of asthma on the epigenome of airway epithelium and provides evidence that aberrant epigenomic mechanisms exert functional consequences in key cell types of asthma, validating the combination of genome-wide and epigenome-editing approaches in identifying and deciphering the molecular mechanisms underlying asthma pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109894 | GEO | 2019/06/04

REPOSITORIES: GEO

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Project description:Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced changes in DNAm in airway epithelial cells and assess the potential functional consequences and biological pathways implicated. We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study (EWAS) using paired nasal epithelial cultures from Puerto Rican children (n=97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p<9x10-8). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p-value=3.3x10-5). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR]<0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p=0.030). DNAm changes in these three CpGs showed to be influenced by three independent genetic variants (FDR<0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30x10 14≤p≤6.60x10-5). Additionally, the hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with reduced gene expression of the genes where they are located (FDR<0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p=0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways) and that albuterol-affected genes are likely regulated by Trichostatin A (FDR<0.05). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p-value<0.05). In conclusion, this study reveals, for the first time, evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma

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Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium.

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