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COPD is Associated with Epigenome-wide Differential Methylation in BAL Lung Cells

ABSTRACT: DNA methylation patterns in chronic pulmonary obstructive disease (COPD) might offer new insights into disease pathogenesis. To assess methylation profiles in the main COPD target organ, we performed an epigenome-wide association study on bronchoalveolar lavage (BAL) cells. Bronchoscopies were performed in 18 COPD subjects and 15 controls (ex- and current smokers). DNA methylation was measured with Illumina MethylationEPIC BeadChip covering >850,000 CpGs. Differentially methylated positions (DMPs) were examined for 1) enrichment in pathways and functional gene relationships using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology; 2) accelerated aging using Horvath’s epigenetic clock; 3) correlation with gene expression; and 4) colocalization with genetic variation. We found 1,155 Bonferroni significant (P < 6.74 × 10-8) DMPs associated with COPD, many with large effect sizes. Functional analysis identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. Strong correlation was found between DNA methylation and chronological age, but not between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL cells. Thirty-nine percent of DMPs were co-localized with COPD-associated SNPs. To the best of our knowledge, this is the first EWAS of COPD on BAL cells, and our analyses revealed many differential methylation sites. Integration with mRNA data showed a strong functional readout for relevant genes, identifying sites where DNA methylation might directly impact expression. Almost half of DMPs were co-located with SNPs identified in previous GWAS of COPD, suggesting joint genetic and epigenetic pathways related to disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198870 | GEO | 2022/03/17

REPOSITORIES: GEO

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Project description:Background While smoking is known to associate with development of multiple diseases, the underlying mechanisms are still poorly understood. Tobacco smoking can modify the chemical integrity of DNA leading to changes in transcriptional activity, partly through an altered epigenetic state. We aimed to investigate the impact of smoking on lung cells collected from bronchoalveolar lavage (BAL). Methods We profiled changes in DNA methylation (5mC) and its oxidized form hydroxymethylation (5hmC) using conventional bisulfite (BS) treatment and oxidative bisulfite treatment with Illumina Infinium MethylationEPIC BeadChip, and examined gene expression by RNA-seq in healthy smokers. Findings We identified 1,667 BS methyl (5mC+5hmC), 1,756 5mC and 67 5hmC differentially methylated positions (DMPs) between smokers and nonsmokers (FDR <0.05, absolute Δβ >0.15). Both 5mC DMPs and to a lesser extent BS methyl (5mC+5hmC) were predominantly hypomethylated. In contrast, almost all 5hmC DMPs were hypermethylated, supporting the hypothesis that smoking-associated oxidative stress can lead to DNA demethylation, via the established sequential oxidation of which 5hmC is the first step. While we confirmed differential methylation of previously reported smoking-associated BS methyl CpGs using former generations of BeadChips in alveolar macrophages, the large majority of identified DMPs, BS methyl (1,639/1,667), 5mC (1,738/1,756), and 5hmC (67/67), have not been previously reported. Most of these novel smoking-associating sites are specific to the EPIC BeadChip and, interestingly, many of them are associated to FANTOM5 enhancers. Transcriptional changes affecting 633 transcripts were consistent with DNA methylation profiles and converged to alteration of genes involved in migration, signaling and inflammatory response of immune cells. Interpretation Collectively, these findings suggest that tobacco smoke exposure epigenetically modifies BAL cells, possibly involving a continuous active demethylation and subsequent increased activity of inflammatory processes in the lungs. -

Project description:Background: Nasal epithelia are emerging as a proxy measure of gene expression of the airway epithelium in asthma. We hypothesized that epigenetic marks regulate gene expression of the nasal epithelia and consequently may provide a novel target for allergic asthma. Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma [N=36] versus healthy controls [N=36]. Results were validated in an independent population of asthmatics [N=30]. Results: We identified 186 genes with significant methylation changes, either as regions (differentially methylated regions [DMRs]) or single CpGs (differentially methylated probes [DMPs]) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. The methylation changes are large (median 9.5%, range: 2.6-29.5% methylation change) and similar in magnitude to those observed in malignancies. Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. Conclusions: Our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner-city children provide new targets for biomarker development, and novel approaches to understanding disease pathogenesis. case control design with nasal epithelial cells from 36 atopic asthmatic and 36 nonatopic nonasthmatic children from the inner city

Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease of the lungs that is currently the fourth leading cause of death worldwide. Genetic factors account for only a small amount of COPD risk, but epigenetic mechanisms including DNA methylation, have the potential to mediate the interactions between an individual?s genetics and environmental exposure. DNA methylation is highly cell type specific and individual cell type studies of DNA methylation in COPD are sparse. Fibroblasts are present within the airway and parenchyma of the lung and contribute to the aberrant deposition of extracellular matrix in COPD. No assessment or comparison of genome-wide DNA methylation profiles in airway and parenchymal fibroblasts from individuals with and without COPD has been undertaken. These data provide valuable insight into the molecular mechanisms contributing to COPD and the differing pathologies of small airways disease and emphysema in COPD. Methods: Genome-wide DNA methylation was evaluated at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip array in airway (non-COPD n=8, COPD n=7) and parenchymal fibroblasts (non-COPD n=18, COPD n=28) isolated from individuals with and without COPD. Targeted gene expression was assessed by qPCR in matched RNA samples. Results: Differentially methylated DNA regions were identified between cells isolated from individuals with and without COPD in both airway and parenchymal fibroblasts. Only in parenchymal fibroblasts was differential DNA methylation associated with differential gene expression. A second analysis of differential DNA methylation variability identified 359 individual differentially variable CpG sites in parenchymal fibroblasts. No differentially variable CpG sites were identified in airway fibroblasts. Five differentially variable methylated CpG sites, associated with three genes were subsequently assessed for gene expression differences. Two genes (OAT and GRIK2) displayed significantly increased gene expression in cells isolated from individuals with COPD. Conclusions: Differential and variable DNA methylation was associated with COPD status in parenchymal fibroblasts but not airway fibroblasts. Aberrant DNA methylation was associated with altered gene expression imparting biological function to DNA methylation changes. Changes in DNA methylation are therefore implicated in the molecular mechanisms underlying COPD pathogenesis and may represent novel therapeutic targets.

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COPD is Associated with Epigenome-wide Differential Methylation in BAL Lung Cells

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