Abstract
Smoking-related lung tumors are characterized by profound epigenetic changes including scrambled patterns of DNA methylation, deregulated histone acetylation, altered gene expression levels, distorted microRNA profiles, and a global loss of cytosine hydroxymethylation marks. Here, we employed an enhanced version of bisulfite sequencing (RRBS/oxRRBS) followed by next generation sequencing to separately map DNA epigenetic marks 5-methyl-dC and 5-hydroxymethyl-dC in genomic DNA isolated from lungs of A/J mice exposed whole-body to environmental cigarette smoke for 10 weeks. Exposure to cigarette smoke significantly affected the patterns of cytosine methylation and hydroxymethylation in the lungs. Differentially hydroxymethylated regions were associated with inflammatory response/disease, organismal injury, and respiratory diseases and were involved in regulation of cellular development, function, growth, and proliferation. To identify epigenetic changes in the lung associated with exposure to tobacco carcinogens and inflammation, A/J mice were intranasally treated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the inflammatory agent lipopolysaccharide (LPS), or both. NNK alone caused minimal epigenetic alterations, while exposure either to LPS or NNK/LPS in combination led to increased levels of global cytosine methylation and formylation, reduced cytosine hydroxymethylation, decreased histone acetylation, and altered expression levels of multiple genes. Our results suggest that inflammatory processes are responsible for epigenetic changes contributing to lung cancer development.
Highlights
Smoking-related lung tumors are characterized by profound epigenetic changes including scrambled patterns of DNA methylation, deregulated histone acetylation, altered gene expression levels, distorted microRNA profiles, and a global loss of cytosine hydroxymethylation marks
In the smoking (ECS) study, A/J mice were treated with cigarette smoke for 10 weeks starting at birth with or without oral co-administration of the nonsteroidal anti-inflammatory agent acetylsalicylic acid on weeks 4–108
While the exact mechanisms by which inflammation contributes to lung tumor development are unknown, early epigenetic changes associated with inflammation have been proposed to play a key role in this process[5]
Summary
Smoking-related lung tumors are characterized by profound epigenetic changes including scrambled patterns of DNA methylation, deregulated histone acetylation, altered gene expression levels, distorted microRNA profiles, and a global loss of cytosine hydroxymethylation marks. To identify epigenetic changes in the lung associated with exposure to tobacco carcinogens and inflammation, A/J mice were intranasally treated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the inflammatory agent lipopolysaccharide (LPS), or both. Smoking-induced lung tumors are characterized by genetic alterations in tumor suppressor genes and protooncogenes, as well as epigenetic changes which include deregulated DNA methylation, altered histone acetylation, and aberrant microRNA expression[9]. Aberrant DNA methylation patterns in malignant cells result in silencing of tumor suppressor genes, activation of protooncogenes, and decreased chromosomal stability[10] These “epimutations” are thought to cooperate with genetic alterations to drive the malignant lung tumor p henotype[9]. The nature and the mechanistic origins of smoking-induced epigenetic deregulation remain largely unknown, limiting our understanding of cancer etiology and hindering the development of future treatments
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