Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium

Abstract

BackgroundAsthma is a chronic airway disease driven by complex genetic–environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood.MethodsWe piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma (n = 4) and healthy controls (n = 3).ResultsWe identified n = 4,321 (FDR < 0.05) regions exhibiting differential H3K27ac enrichment between asthma and health, clustering at genes associated predominately with epithelial processes (EMT). We identified initial evidence of asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (PTGS1). We integrated published datasets to identify epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and identify initial relationships between asthma-associated changes in H3K27ac and transcriptional profiles. Finally, we investigated the potential of CRISPR-based approaches to functionally evaluate H3K27ac-asthma landscape in vitro by identifying guide-RNAs capable of targeting acetylation to asthma DERs and inducing gene expression (TLR3).ConclusionOur small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.

Role of Histone Post-Translational Modifications in Inflammatory Diseases

“…When p300 expression and HAT activity as well as aceH3 levels were impeded by C646, the expression of ORMDL3 would be reduced and relieve airway hyperreactivity, which improves airway inflammation and remodeling in asthma ( 153 ). With a genome-wide profiling of the enhancer-associated histone modification H3K27ac in bronchial epithelial cells (BECs) from asthma patients, 4,321 (FDR < 0.05) regions were identified to exhibit differential H3K27ac enrichment between individuals with or without asthma ( 154 ). Inhibiting H3K27me3 demethylation by a selective inhibitor GSK-J4 could improve the typical hallmarks of asthma, including airway inflammation, hyperresponsiveness, and remodeling, then alleviate the development of asthmatic disease ( 155 ).…”

Decoding the genetic and epigenetic basis of asthma

“…Numerous studies have mapped GWAS SNPs to cell type‐specific GREs, supporting the concept of disease‐associated “regulatory SNPs” underlying human traits and disease 9,89,91,93,117 . For asthma, epigenomics data have been used to link enhancer regions in CD4 + T cells, ILC2s, and BECs to asthma susceptibility 58,118–121 . For example, Seumois et al used H3K4Me2 ChIP‐Seq of circulating Th2 cells to show that GWAS SNPs are enriched in Th2‐specific GREs, and that some of these GREs exhibited differential H3K4Me2 levels in cells from asthma patients compared with healthy controls 118 .…”

“…Moreover, eQTL effects were highly cell type‐specific with substantial differences across airway epithelial cells, endothelial cells, and T cells. How non‐coding variants affect IL1RL1 regulation remains unclear, although the IL1RL1 promoter regions appear particularly enriched for GWAS SNPs, as was shown for activated human ILC2s 119 and for human BECs from asthma patients 120 …”

“…9,89,91,93,117 For asthma, epigenomics data have been used to link enhancer regions in CD4 + T cells, ILC2s, and BECs to asthma susceptibility. 58,[118][119][120][121] For example,…”

Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma

“…One previous study utilized scRNA-seq to identify cell type-specific effects of IL-13 stimulation on cultured human tracheal epithelial cells. 22 Another study 23 used H3K27ac profiling to compare the regulatory landscape of cells cultured from healthy control individuals and individuals with asthma, although these cells were cultured under conditions that do not promote cell differentiation, and the effects of IL-13 stimulation were not studied. Because there are important differences between the airway epithelial sample types used across these previous studies, we chose to use a single model that has been well characterized in our prior studies 11 , 13 , 24 to allow us to better associate gene expression and epigenetic changes.…”