title: Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression.
abstract: Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.
authors.affiliation: Departments of Psychiatry, The University of Iowa, Iowa City, IA, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Philibert
authors.forename: Rory A
authors.initials: RA
authors.lastname: Sears
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.forename: Emma
authors.initials: E
authors.lastname: Nash
authors.forename: Thomas
authors.initials: T
authors.lastname: Bair
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Gerke
authors.forename: Ihab
authors.initials: I
authors.lastname: Hassan
authors.forename: Christie P
authors.initials: CP
authors.lastname: Thomas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gross
authors.forename: Martha M
authors.initials: MM
authors.lastname: Monick
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D016676:Macrophages, Alveolar; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1