Altered DNA methylation is associated with aberrant gene expression in parenchymal but not airway fibroblasts isolated from individuals with COPD

Abstract

BackgroundChronic 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 the 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.MethodsGenome-wide DNA methylation was evaluated at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip array in the airway (non-COPD n = 8, COPD n = 7) and parenchymal fibroblasts (non-COPD n = 17, COPD n = 29) isolated from individuals with and without COPD. Targeted gene expression was assessed by qPCR in matched RNA samples.ResultsDifferentially 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 the 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.ConclusionsDifferential and variable DNA methylation was associated with COPD status in the 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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0464-5) contains supplementary material, which is available to authorized users.

Variations in BCO2 Coding Sequence Causing a Difference in Carotenoid Concentration in the Skin of Chickens

“…CNVs in the testis-speci c Y-encoded protein (TSPY) gene have been linked to prostate cancer and human male infertility [23][24][25]. CNVs in the stem cell factor receptor (KIT) gene are linked to porcine white coat color [26], while CNVs in the agouti signaling protein (ASIP) gene in uences coat color of goat breeds [27]. We detected in the present study CNVs in BOC2, the copy number in the Qingjiao Ma (white skin chicken) being almost 2-fold larger than in the Guangxi Huang (yellow skin chicken) breed, suggesting that a lower CNV may lead to down-regulation of BCO2 expression.…”

DNA Methylation: A Potential Biomarker of Chronic Obstructive Pulmonary Disease

“…DNAm has a high level of cell-type specificity, there are some studies on DNAm of individual cell types in patients with COPD. Clifford et al (2018) had studied the genomic DNAm of fibroblasts isolated from lung parenchyma and airway, and found DNAm to be related to differential gene expression only in the parenchymal fibroblasts. In addition, 359 individual differential CpG loci were found in the parenchymal fibroblasts.…”

“…In addition, 359 individual differential CpG loci were found in the parenchymal fibroblasts. The methylation sites of OAT and GRIK2 genes significantly increased their expression in COPD cells ( Clifford et al, 2018 ). Barnawi et al (2017) had found phagocytosis of apoptotic cells by alveolar macrophages in patients with COPD to be controlled by epigenetic regulation, and decrease of methylation to possibly be the cause of increased S1PR5 gene expression in alveolar macrophages and of the defect in COPD-related efferent cells.…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…Genome‐wide DNA methylation profiles and gene expression analyses in parenchymal cells, small airways and lung tissue suggest that aberrant DNA methylation patterns occur in numerous genes linked to functions and pathways important to COPD (Clifford et al, ; Morrow et al, ; Vucic et al, ). In a study examining homogenized lung tissue samples from patients with COPD, the top differentially methylated sites included cholinergic receptor muscarinic 1 (M 1 ), which is related to the PI3K‐Akt signalling pathway and bronchoconstriction of the airways, as well as glycosyltransferase 1 domain containing 1 ( GLT1D1 ) and deltex E3 ubiquitin ligase 1 ( DTX1 ), implicated respectively in reduced responses to LT modifiers in the treatment of asthma and in the development of natural killer T cells through regulating Notch signalling (Morrow et al, ).…”

“…Genome-wide DNA methylation profiles and gene expression analyses in parenchymal cells, small airways and lung tissue suggest that aberrant DNA methylation patterns occur in numerous genes linked to functions and pathways important to COPD (Clifford et al, 2018;Morrow et al, 2018;Vucic et al, 2014). In a study examining F I G U R E 3 DNA methylation and demethylation occur through passive and active mechanisms.…”