Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers.
Smoking is associated with a wide variety of adverse health outcomes including cancer, chronic obstructive pulmonary disease, diabetes, depression, and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in these processes, we examined the relationship of smoking to genome wide methylation and gene expression using biomaterial from two independent samples, lymphoblast DNA and RNA (n = 119) and lung alveolar macrophage DNA (n = 19). We found that in both samples current smoking status was associated with significant changes in DNA methylation, in particular at the aryl hydrocarbon receptor repressor (AHRR), a known tumor suppressor. Both baseline DNA methylation and smoker associated DNA methylation signatures at AHRR were highly correlated (r = 0.94 and 0.45, respectively). DNA methylation at the most differentially methylated AHRR CpG residue in both samples, cg0557592, was significantly associated with AHRR gene expression. Pathway analysis of lymphoblast data (genes with most significant methylation changes) demonstrated enrichment in protein kinase C pathways and in TGF beta signaling pathways. For alveolar macrophages, pathway analysis demonstrated alterations in inflammation-related processes. We conclude that smoking is associated with functionally significant genome wide changes in DNA methylation in both lymphoblasts and pulmonary macrophages and that further integrated investigations of these epigenetic effects of smoking on carcinogenesis and other related co-morbidities are indicated.
Department of Medicine, The University of Iowa, Iowa City, USA.
Martha M
MM
Monick
Steven R H
SR
Beach
Jeff
J
Plume
Rory
R
Sears
Meg
M
Gerrard
Gene H
GH
Brody
Robert A
RA
Philibert
D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012907:Smoking / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004247:DNA; D012097:Repressor Proteins; C492162:AHRR protein, human