DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

Tekpli, Xavier; Zienolddiny, Shanbeh; Skaug, Vidar; Stangeland, Lodve; Haugen, Aage; Mollerup, Steen

doi:10.1002/ijc.27421

Cited by 58 publications

(58 citation statements)

References 34 publications

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“…However, our findings are supported by other publications which have demonstrated in whole-lung tissue as well as macrophages that genes involved in the metabolism of xenobiotics by cytochrome P450 and aryl hydrocarbon signaling are differentially methylated in response to cigarette smoking (18)(19)(20). This suggests the importance of epigenetic regulation of these pathways in response to cigarette smoke.…”

Section: Smoking-associated Changes In Lung Dna Methylationsupporting

confidence: 91%

“…Similar to other studies, we observed alterations in DNA methylation levels of cytochrome P450 genes in response to smoking. For example, CYP1A1 displayed lower DNA methylation levels in smokers compared with nonsmokers in lung tissue (18,19). Anttila et al (19) also observed an increase in DNA methylation levels of CYP1A1 in active smokers who had quit smoking 1 to 7 days earlier.…”

Section: Smoking-associated Changes In Lung Dna Methylationmentioning

confidence: 99%

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Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Buro-Auriemma

Salit

Hackett

et al. 2013

Human Molecular Genetics

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The small airway epithelium (SAE), the first site of smoking-induced lung pathology, exhibits genome-wide changes in gene expression in response to cigarette smoking. Based on the increasing evidence that the epigenome can respond to external stimuli in a rapid manner, we assessed the SAE of smokers for genome-wide DNA methylation changes compared with nonsmokers, and whether changes in SAE DNA methylation were linked to the transcriptional output of these cells. Using genome-wide methylation analysis of SAE DNA of nonsmokers and smokers, the data identified 204 unique genes differentially methylated in SAE DNA of smokers compared with nonsmokers, with 67% of the regions with differential methylation occurring within 2 kb of the transcriptional start site. Among the genes with differential methylation were those related to metabolism, transcription, signal transduction and transport. For the differentially methylated genes, 35 exhibited a correlation with gene expression, 54% with an inverse correlation of DNA methylation with gene expression and 46% a direct correlation. These observations provide evidence that cigarette smoking alters the DNA methylation patterning of the SAE and that, for some genes, these changes are associated with the smoking-related changes in gene expression.

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Section: Smoking-associated Changes In Lung Dna Methylationsupporting

confidence: 91%

Section: Smoking-associated Changes In Lung Dna Methylationmentioning

confidence: 99%

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Buro-Auriemma

Salit

Hackett

et al. 2013

Human Molecular Genetics

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“…In occasional examples, enhancer methylation level has been suggested to be associated with the control of cancer-related genes[35-37]. However, to our knowledge this is the first report on a global association between perturbed enhancer methylation and aberrant expression of cancer genes.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes

Aran

Sabato

Hellman³

2013

Genome Biol

302

279

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BackgroundAbnormal epigenetic marking is well documented in gene promoters of cancer cells, but the study of distal regulatory siteshas lagged behind.We performed a systematic analysis of DNA methylation sites connected with gene expression profilesacross normal and cancerous human genomes.ResultsUtilizing methylation and expression data in 58 cell types, we developed a model for methylation-expression relationships in gene promoters and extrapolated it to the genome. We mapped numerous sites at which DNA methylation was associated with expression of distal genes. These sites bind transcription factors in a methylation-dependent manner, and carry the chromatin marks of a particular class of transcriptional enhancers. In contrast to the traditional model of one enhancer site per cell type, we found that single enhancer sites may define gradients of expression levels across many different cell types. Strikingly, the identified sites were drastically altered in cancers: hypomethylated enhancer sites associated with upregulation of cancer-related genes and hypermethylated sites with downregulation. Moreover, the association between enhancer methylation and gene deregulation in cancerwas significantly stronger than the association of promoter methylationwith gene deregulation.ConclusionsMethylation of distal regulatory sites is closely related to gene expression levels across the genome. Single enhancers may modulate ranges of cell-specific transcription levels, from constantlyopen promoters. In contrast to the remote relationships between promoter methylation and gene dysregulation in cancer, altered methylation of enhancer sites is closely related to gene expression profiles of transformed cells.

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“…Joubert et al (2012) used the 450K methylation bead chip (Illumina) and their top hit was also AHRR . There are also several reports of smoking-associated changes in global DNA methylation as well as changes in candidate genes (Breitling et al 2012; Hillemacher et al 2008; Kiseljak-Vassiliades and Xing 2011; Philibert et al 2010; Smith et al 2007; Tekpli et al 2012; Wolff et al 2008; Zhang et al 2011). …”

Section: Introductionmentioning

confidence: 99%

CpG Sites Associated with Cigarette Smoking: Analysis of Epigenome-Wide Data from the Sister Study

Harlid

Panduri

et al. 2014

Environ Health Perspect

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Background: Smoking increases the risk of many diseases, and it is also linked to blood DNA methylation changes that may be important in disease etiology.Objectives: We sought to identify novel CpG sites associated with cigarette smoking.Methods: We used two epigenome-wide data sets from the Sister Study to identify and confirm CpG sites associated with smoking. One included 908 women with methylation measurements at 27,578 CpG sites using the HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the HumanMethylation450 BeadChip. Significant CpGs from the second data set that were not included in the 27K assay were validated by pyrosequencing in a subset of 476 samples from the first data set.Results: Our study successfully confirmed smoking associations for 9 previously established CpGs and identified 2 potentially novel CpGs: cg26764244 in GNG12 (p = 9.0 × 10–10) and cg22335340 in PTPN6 (p = 2.9 × 10–05). We also found strong evidence of an association between smoking status and cg02657160 in CPOX (p = 7.3 × 10–7), which has not been previously reported. All 12 CpGs were undermethylated in current smokers and showed an increasing percentage of methylation in former and never-smokers.Conclusions: We identified 2 potentially novel smoking related CpG sites, and provided independent replication of 10 previously reported CpGs sites related to smoking, one of which is situated in the gene CPOX. The corresponding enzyme is involved in heme biosynthesis, and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation.Citation: Harlid S, Xu Z, Panduri V, Sandler DP, Taylor JA. 2014. CpG sites associated with cigarette smoking: analysis of epigenome-wide data from the Sister Study. Environ Health Perspect 122:673–678; http://dx.doi.org/10.1289/ehp.1307480

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DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

Cited by 58 publications

References 34 publications

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes

CpG Sites Associated with Cigarette Smoking: Analysis of Epigenome-Wide Data from the Sister Study

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