title: DNA methylation is globally disrupted and associated with expression changes in chronic obstructive pulmonary disease small airways.
abstract: DNA methylation is an epigenetic modification that is highly disrupted in response to cigarette smoke and involved in a wide spectrum of malignant and nonmalignant diseases, but surprisingly not previously assessed in small airways of patients with chronic obstructive pulmonary disease (COPD). Small airways are the primary sites of airflow obstruction in COPD. We sought to determine whether DNA methylation patterns are disrupted in small airway epithelia of patients with COPD, and evaluate whether changes in gene expression are associated with these disruptions. Genome-wide methylation and gene expression analysis were performed on small airway epithelial DNA and RNA obtained from the same patient during bronchoscopy, using Illumina's Infinium HM27 and Affymetrix's Genechip Human Gene 1.0 ST arrays. To control for known effects of cigarette smoking on DNA methylation, methylation and gene expression profiles were compared between former smokers with and without COPD matched for age, pack-years, and years of smoking cessation. Our results indicate that aberrant DNA methylation is (1) a genome-wide phenomenon in small airways of patients with COPD, and (2) associated with altered expression of genes and pathways important to COPD, such as the NF-E2-related factor 2 oxidative response pathway. DNA methylation is likely an important mechanism contributing to modulation of genes important to COPD pathology. Because these methylation events may underlie disease-specific gene expression changes, their characterization is a critical first step toward the development of epigenetic markers and an opportunity for developing novel epigenetic therapeutic interventions for COPD.
authors.affiliation: 1 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.forename: Raj
authors.initials: R
authors.lastname: Chari
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Ian M
authors.initials: IM
authors.lastname: Wilson
authors.forename: Allison M
authors.initials: AM
authors.lastname: Cotton
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Kennett
authors.forename: May
authors.initials: M
authors.lastname: Zhang
authors.forename: Kim M
authors.initials: KM
authors.lastname: Lonergan
authors.forename: Katrina
authors.initials: K
authors.lastname: Steiling
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Brown
authors.forename: Annette
authors.initials: A
authors.lastname: McWilliams
authors.forename: Keishi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Calum E
authors.initials: CE
authors.lastname: Macaulay
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000368:Aged; D001980:Bronchi / Q000378:metabolism; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D004848:Epithelium / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D012907:Smoking / Q000235:genetics / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D012313:RNA; D004247:DNA