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Öğe Environmental epitranscriptomics(Academic Press Inc Elsevier Science, 2020) Cayir, Akin; Byun, Hyang-Min; Barrow, Timothy M.Chemical modifications of RNA molecules have gained increasing attention since evidence emerged for their substantive roles in a range of biological processes, such as the stability and translation of mRNA transcripts. More than 150 modifications have been identified in different organisms to date, collectively known as the 'epitranscriptome', with 6-methyladenosine (m(6)A), 5-methylcytidine (m(5)C), pseudouridine and N1-methyladenosine (m(1)A) the most extensively investigated. Although we are just beginning to elucidate the roles of these modifications in cellular functions, there is already evidence for their dysregulation in diseases such as cancer and neumdevelopmental disorders. There is currently more limited knowledge regarding how environmental exposures affect the epitranscriptome and how this may mediate disease risk, but evidence is beginning to emerge. Here, we review the current evidence for the impact of environmental exposures such as benzo[a]pyrene, bisphenol A, pesticides, metals and nanoparticles upon RNA modifications and the expression of their 'writers' (methyl transferases), 'erasers' (demethylases) and `readers'. We discuss future directions of the field and identify areas of particular promise and consider the technical challenges that are faced.Öğe Exposure to environmental toxicants reduces global N6-methyladenosine RNA methylation and alters expression of RNA methylation modulator genes(Academic Press Inc Elsevier Science, 2019) Cayir, Akin; Barrow, Timothy M.; Guo, Liqiong; Byun, Hyang-MinThe epitranscriptome comprises more than 100 forms of RNA modifications. Of these, N6-methyladenosine (m(6)A) is the most abundant form of RNA methylation, with roles in modulating mRNA transcript processing and regulation. The aims of the study were to examine changes inm(6)A RNA methylation in A549 lung epithelial cells in response to environmental toxicants, and differential gene expression of m(6)A modulator genes ('readers', 'writers' and 'erasers') in human subjects exposed to particulate matter (PM) and in lung cancer tissue using publicly-available microarray datasets. Global m(6)A methylation levels were measured in total RNA after exposure to two carcinogens (PM and sodium arsenite) for 24- and 48-h, and to two endocrine disruptors (bisphenol A and vinclozolin)for 24-h. Global m(6)A methylation level significantly decreased with exposure to > 62 mu g/mlPM, > 1 mu M sodium arsenite, > 1 mu M bisphenol A (BPA), and 0.1 mu M vinclozolin. In an analysis of a published dataset derived from a population study, we observed that m(6)A writers (METTL3 and WTAP), erasers (FTO and ALKBH5) and readers (HNRPC) showed significantly higher expression among participants in the high-PM2.5 exposure group compared to those in the low-exposure control group (all p < 0.05). Further, the m(6)A writer METTL3 shows reduced expression in lung tumors in comparison to normal lung epithelia (p < 0.0001). Our findings reveal that m(6)A RNA methylation can be modified by exposure to environmental toxicants, and exposure to particulate matter is associated with differential expression level of m(6)A RNA methylation modification machinery.Öğe Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity(BMC, 2020) Corsi, Sarah; Iodice, Simona; Vigna, Luisella; Cayir, Akin; Mathers, John C.; Bollati, Valentina; Byun, Hyang-MinBackground The association between obesity and cardiovascular disease (CVD) is proven, but why some adults with obesity develop CVD while others remain disease-free is poorly understood. Here, we investigated whether mitochondrial DNA (mtDNA) methylation in platelets is altered prior to CVD development in a population of adults with overweight and obesity. Methods We devised a nested case-control study of 200 adults with overweight or obesity who were CVD-free at baseline, of whom 84 developed CVD within 5 years, while 116 remained CVD-free. Platelet mtDNA was isolated from plasma samples at baseline, and mtDNA methylation was quantified in mitochondrially encoded cytochrome-C-oxidase I (MT-CO1; nt6797 and nt6807), II (MT-CO2; nt8113 and nt8117), and III (MT-CO3; nt9444 and nt9449); tRNA leucine 1 (MT-TL1; nt3247 and nt3254); D-loop (nt16383); tRNA phenylalanine (MT-TF; nt624); and light-strand-origin-of-replication (MT-OLR; nt5737, nt5740, and nt5743) by bisulfite-pyrosequencing. Logistic regression was used to estimate the contribution of mtDNA methylation to future CVD risk. ROC curve analysis was used to identify the optimal mtDNA methylation threshold for future CVD risk prediction. A model was generated incorporating methylation at three loci (score 0, 1, or 2 according to 0, 1, or 2-3 hypermethylated loci, respectively), adjusted for potential confounders, such as diastolic and systolic blood pressure, fasting blood glucose, and cholesterol ratio. mtDNA methylation at MT-CO1 nt6807 (OR = 1.08, 95% CI 1.02-1.16; P = 0.014), MT-CO3 nt9444 (OR = 1.22, 95% CI 1.02-1.46, P = 0.042), and MT-TL1 nt3254 (OR = 1.30, 95% CI 1.05-1.61, P = 0.008) was higher at baseline in those who developed CVD by follow-up, compared with those who remained CVD-free. Combined use of the three loci significantly enhanced risk prediction, with hazard ratios of 1.38 (95% CI 0.68-2.78) and 2.68 (95% CI 1.41-5.08) for individuals with score 1 or 2, respectively (P = 0.003). Methylation at these sites was independent of conventional CVD risk factors, including inflammation markers, fasting blood glucose concentration, and blood pressure. Conclusions Methylations of MT-CO1, MT-CO3, and MT-TL1 are, together, strong predictors of future CVD incidence. Since methylation of these mtDNA domains was independent of conventional CVD risk factors, these markers may represent a novel intrinsic predictor of CVD risk in adults with overweight and obesity.
