Tobacco smoke exposure can cause DNA methylation changes by activating smoke-responsive enhancers

What is it about?

Changes in DNA methylation in white blood cells of subjects exposed to tobacco smoke have been widely reported. These changes consist largely loss of DNA methylation. Why these changes happen and what their functional consequences might be remains largely unclear. in addition, how such changes in blood cells compare with those seen in other tissues such as the lung has not been well investigated. Here we examined DNA methylation changes in the lung tissue of smokers. We find CpG dinucleotides that lose DNA methylation, and 5 of these are similar to those seen in blood. Two of these CpGs lie next to smoking-responsive enhancers, and loss of methylation might be due to increased activity at these enhancers. Thus, at least in some cases, loss of DNA methylation due to exposure to tobacco smoke appears to be a side effect of the exposure. Changes in DNA methylation can therefore help uncover tobacco smoke-responsive regulatory elements. One CpG for which this is true, is g05575921, which lies in intron 3 of the aryl hydrocarbon receptor repressor gene, a gene that plays a role in down-regulating the response to xenobiotics. Cg05575921 lies on the flanks of a smoke-activated enhancer and appears to turn on the AHRR gene, thus implicating this gene in lung cancer risk.

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Why is it important?

To date many papers report changes in DNA methylation but few examine why these changes might occur. Here we mechanistically investigate regions losing DNA methylation, and show that at least in some cases, such as in the case of cg05575921, loss of methylation appears to be a side effect of the activation of a regulatory element. Cg05575921 is one of the most reported CpGs hypomethylated in response to tobacco smoke exposure, it is highly correlated with lung cancer risk. Our work begins to unravel the link between exposure to tobacco smoke, DNA methylation loss, and lung cancer risk.