DNA methylation in nasal epithelial cells from smokers: identification of ULBP3-related effects

Abstract

-We previously demonstrated that, in nasal epithelial cells (NECs) from smokers, methylation of an antiviral gene was associated with impaired antiviral defense responses. To expand these findings and better understand biological mechanisms underlying cigarette smoke (CS)-induced modifications of host defense responses, we aimed to compare DNA methylation of genes that may play a role in antiviral response. We used a two-tiered analytical approach, where we first implemented a genome-wide strategy. NECs from smokers differed in the methylation levels of 390 genes, the majority (84%) of which showed decreased methylation in smokers. Secondly, we generated an a priori set of 161 antiviral response-related genes, of which five were differentially methylated in NEC from smokers (CCL2, FDPS, GSK3B, SOCS3, and ULBP3). Assessing these genes at the systems biology level revealed a protein interaction network associated with CS-induced epigenetic modifications involving SOCS3 and ULBP3 signaling, among others. Subsequent confirmation studies focused on SOCS3 and ULBP3, which were hypomethylated and hypermethylated, respectively. Expression of SOCS3 was increased, whereas ULBP3 expression was decreased in NECs from smokers. Addition of the demethylating agent 5-Aza-2-deoxycytidine enhanced ULBP3 expression in NECs from smokers. Furthermore, infection of differentiated NECs with influenza virus resulted in significantly lower levels of ULBP3 in cells from smokers. Taken together, our findings show that genomic DNA methylation profiles are altered in NECs from smokers and that these changes are associated with decreased antiviral host defense responses, indicating that epigenenic dysregulation of genes such as SOCS3 and ULBP3 likely impacts immune responses in the epithelium.

DNA methylation analysis of cancer-related genes in oral epithelial cells of healthy smokers

“…As in the present work, some studies have reported epigenetic alterations in healthy samples of smokers and it has been shown in blood cells, [13][14][15][16]68 sputum, small airway epithelium 69 and nasal epithelial cells 70 including studies with MLH1. 20,71 These data are extremely important because, as already suggested, it could be possible to predict cases of cancer, i.e.…”

Will chronic e-cigarette use cause lung disease?

“…This will make studying the chronic effects of E-Cigs difficult since the airways/lung retain a significant memory of smoking history/exposure even after smoking cessation. For example, Rager et al found significant evidence of DNA methylation in the nasal epithelia of ex-smokers (121). Thus, for any observed effects on E-Cig smokers, the previous and/or current tobacco smoking history must be taken into account.…”

Attenuated Airway Epithelial Cell Interleukin-22R1 Expression in the Infant Nonhuman Primate Lung

“…For example, nasal epithelial cells from smokers have unique DNA methylation patterns as compared with nonsmokers, and this results in altered expression of antiviral genes in vitro (18). Taken together, our studies suggest one putative immune pathway by which airway epithelium of very young children may exhibit enhanced susceptibility to pathogens.…”

“…Epigenetic regulation of gene expression in airway epithelium is evident in inflammatory conditions like asthma, smoking, and infection; TSA has been instrumental in uncovering the role of histone acetylation in some of these studies (18,(31)(32)(33). Although TSA is an inhibitor of most of the class I and II HDAC proteins, its activity is restricted outside of the HDAC family of proteins (34).…”