Scope
Alterations in DNA methylation patterns are correlated with aging, environmental exposures, and disease pathophysiology; the possibility of reverting or preventing these processes through ...dietary intervention is gaining momentum. In particular, methyl donors that provide S‐adenosyl‐methionine for one‐carbon metabolism and polyphenols such as flavanols that inhibit the activity of DNA methyltransferases (DNMTs) can be key modifiers of epigenetic patterns.
Methods and results
DNA methylation patterns are assessed in publicly available Illumina Infinium 450K methylation datasets from intervention studies with either folic acid + vitamin B12 (GSE74548) or monomeric and oligomeric flavanols (MOF) (GSE54690) in 44 and 13 participants, respectively. Global DNA methylation levels are increased in unmethylated regions such as CpG islands and shores following folic acid + vitamin B12 supplementation and decreased in highly methylated regions, including shelves and open‐seas, following intervention with MOF. After supplementation with folic acid + vitamin B12, epigenetic age, estimated by the Horvath “epigenetic clock” model, is reduced in women with the MTHFR 677CC genotype.
Conclusions
The effects of supplementation with folic acid + vitamin B12 and MOF on DNA methylation age are dependent upon gender and MTHFR genotype. Additionally, the findings demonstrate the potential for these dietary factors to modulate global DNA methylation profiles.
The effects of dietary supplementation with folic acid + vitamin B12 and flavanols upon global epigenetic patterns and epigenetic age are examined. Increased methylation at CpG islands and shores following folic acid + vitamin B12, and decreased methylation at shelf and open sea regions after flavanols supplementation, are observed. Epigenetic age is decelerated by folic acid + vitamin B12, but only in women with MTHFR 677CC.
Prenatal exposure to tobacco smoke increases the risk for diseases later in the child's life that may be mediated through alterations in DNA methylation.
To demonstrate that differences in DNA ...methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations.
Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and pyrosequencing in buccal cells of 348 children participating in the Children's Health Study. Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 participants in the Children's Health Study children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by pyrosequencing. Estimates were standardized across loci using a Z score to enable cross-comparison of results.
DNA methylation patterns were associated with in utero exposure to maternal smoking. Exposed children had significantly lower methylation of AluYb8 (beta, -0.31; P = 0.03). Differences in smoking-related effects on LINE1 methylation were observed in children with the common GSTM1 null genotype. Differential methylation of CpG loci in eight genes was identified through the screen. Two genes, AXL and PTPRO, were validated by pyrosequencing and showed significant increases in methylation of 0.37 (P = 0.005) and 0.34 (P = 0.02) in exposed children. The associations with maternal smoking varied by a common GSTP1 haplotype.
Life-long effects of in utero exposures may be mediated through alterations in DNA methylation. Variants in detoxification genes may modulate the effects of in utero exposure through epigenetic mechanisms.
Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. Here we performed comprehensive genome-scale DNA ...methylation profiling of 125 colorectal tumors and 29 adjacent normal tissues. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. A CIMP-high (CIMP-H) subgroup, which exhibits an exceptionally high frequency of cancer-specific DNA hypermethylation, is strongly associated with MLH1 DNA hypermethylation and the BRAF(V600E) mutation. A CIMP-low (CIMP-L) subgroup is enriched for KRAS mutations and characterized by DNA hypermethylation of a subset of CIMP-H-associated markers rather than a unique group of CpG islands. Non-CIMP tumors are separated into two distinct clusters. One non-CIMP subgroup is distinguished by a significantly higher frequency of TP53 mutations and frequent occurrence in the distal colon, while the tumors that belong to the fourth group exhibit a low frequency of both cancer-specific DNA hypermethylation and gene mutations and are significantly enriched for rectal tumors. Furthermore, we identified 112 genes that were down-regulated more than twofold in CIMP-H tumors together with promoter DNA hypermethylation. These represent ∼7% of genes that acquired promoter DNA methylation in CIMP-H tumors. Intriguingly, 48/112 genes were also transcriptionally down-regulated in non-CIMP subgroups, but this was not attributable to promoter DNA hypermethylation. Together, we identified four distinct DNA methylation subgroups of CRC and provided novel insight regarding the role of CIMP-specific DNA hypermethylation in gene silencing.
Environmental epitranscriptomics Cayir, Akin; Byun, Hyang-Min; Barrow, Timothy M.
Environmental research,
October 2020, 2020-10-00, Letnik:
189
Journal Article
Recenzirano
Odprti dostop
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 (m6A), 5-methylcytidine (m5C), pseudouridine and N1-methyladenosine (m1A) 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 neurodevelopmental 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 benzoapyrene, 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.
Background
The mitochondrion is the primary target of oxidative stress in response to exogenous environments. Mitochondrial DNA (mtDNA) is independent from nuclear DNA and uses separate epigenetic ...machinery to regulate mtDNA methylation. The mtDNA damage induced by oxidative stress can cause mitochondrial dysfunction and is implicated in human diseases; however, mtDNA methylation has been largely overlooked in environmental studies relating to human disease. The purpose of this study was to examine the association between exposure to fine metal‐rich particulates (particulate matter <2.5 µm in diameter PM2.5) from welding in a boilermaker union and blood mtDNA methylation in relation to heart rate variability.
Methods and Results
Forty‐eight healthy men were recruited on multiple sampling cycles at the Boilermaker Union Local 29, located in Quincy, Massachusetts. We measured personal PM2.5 in the background ambient environment. We measured blood mtDNA methylation in the mtDNA promoter (D‐loop) and genes essential for ATP synthesis (MT‐TF and MT‐RNR1) by bisulfite pyrosequencing. All analyses were adjusted for demographics, type of job, season, welding‐work day, and mtDNA methylation experimental batch effect. The participants’ PM2.5 exposure was significantly higher after a welding‐work day (mean 0.38 mg/m3) than the background personal level (mean 0.15 mg/m3, P<0.001). Blood mtDNA methylation in the D‐loop promoter was associated with PM2.5 levels (β=−0.99%, SE=0.41, P=0.02). MT‐TF and MT‐RNR1 methylation was not associated with PM2.5 exposure (β=0.10%, SE=0.45, P=0.82). Interaction of PM2.5 exposure levels and D‐loop promoter methylation was significantly associated with markers of heart rate variability.
Conclusions
Blood mtDNA methylation levels were negatively associated with PM2.5 exposure and modified the adverse relationships between PM2.5 exposure and heart rate variability outcomes.
While previous studies have demonstrated that prenatal exposure to environmental stressors is associated with mitochondrial DNA (mtDNA) methylation, more recent investigations are questioning the ...accuracy of the methylation assessment and its biological relevance. In this study, we investigated placental mtDNA methylation while accounting for methodological issues such as nuclear contamination, bisulphite conversion, and PCR bias. From the ENVIR
AGE birth cohort, we selected three groups of participants (n = 20/group). One group with mothers who smoked during pregnancy (average 13.2 cig/day), one group with high air pollutant exposure (PM
: 16.0 ± 1.4 µg/m
, black carbon: 1.8 ± 0.3 µg/m
) and one control group (non-smokers, PM
: 10.6 ± 1.7 µg/m
, black carbon: 0.9 ± 0.1 µg/m
) with low air pollutant exposure. DNA methylation levels were quantified in two regions of the displacement loop control region (
and
) by bisulphite pyrosequencing. Additionally, we measured DNA methylation on nuclear genes involved in mitochondrial maintenance (
, and
) and assessed mtDNA content using qPCR. Absolute
methylation levels were higher for mothers that smoked extensively (+0.36%, 95% CI: 0.06% to 0.66%), and for mothers that were highly exposed to air pollutants (+0.47%, 95% CI: 0.20% to 0.73%). The relevance of our findings is further supported, as
methylation levels were correlated with placental mtDNA content (r = -0.40, p = 0.002) and associated with birth weight (-106.98 g, 95% CI: -209.60 g to -4.36 g for an IQR increase in
methylation). Most notably, our data demonstrates relevant levels of mtDNA methylation in placenta tissue, with significant associations between prenatal exposure to environmental stressors and
methylation.
Investigations on the potential effects of high air pollution exposure before pregnancy on adverse pregnancy outcomes are limited, and it is unknown whether air quality standards looser than that set ...by World Health Organization (WHO) still can provide sufficient protection pregnant women from adverse pregnancy outcomes.
To evaluate the potential effects of high ambient air pollution around pregnancy on preterm birth (PTB) and low birth weight (LBW), and assess the risk of PTB and LBW associated with air pollutants with reference to different air quality standards of WHO and China.
Our study leveraged 10,960 pregnant women from the Project ELEFANT. Daily average particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5) and ≤10 μm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) concentrations were collected based on Chinese Air Quality Reanalysis datasets. Hazard ratios (HR) of PTB and LBW were estimated for maternal PM2.5, PM10, NO2, SO2, CO and O3 exposures and related proportions of days with daily average air pollution concentrations exceeding air quality standards of WHO and China around pregnancy using Cox proportional hazards regression models with adjustment for potential confounders.
Ambient PM2.5, PM10, NO2, SO2 and CO exposure during the before pregnancy and pregnancy period were both significantly and positively associated with increased risk of PTB, PTB subtypes and LBW. A 10% increase in proportion of days with daily average PM2.5 exceeding 25 μg/m3 over the entire pregnancy was most apparently associated with risk of PTB (HR, 12.66; 95% CI, 8.20–19.53) and LBW (HR, 17.42; 95% CI, 6.88–44.10) among all PM2.5 proportion variables based on different air quality standards.
Air quality standards of WHO are necessary to be implemented to control for risks of adverse pregnancy outcomes associated with ambient air pollution in areas with high air pollution levels.
Display omitted
•High ambient air pollution exposure was associated with risks of PTB and LBW.•Before pregnancy period was also a susceptible exposure window.•Stricter air quality standards are helpful to control for risks of PTB and LBW.•Implementing AQGs of WHO is imperative for areas with high air pollution levels.
Among nondiabetic individuals, higher fasting blood glucose (FBG) independently predicts diabetes risk, cardiovascular disease, and dementia. Ambient PM2.5 (particulate matter with aerodynamic ...diameter ≤ 2.5 μm) is an emerging determinant of glucose dysregulation. PM2.5 effects and mechanisms are understudied among nondiabetic individuals.
Our goals were to investigate whether PM2.5 is associated with an increase in FBG and to explore potential mediating roles of epigenetic gene regulation.
In 551 nondiabetic participants in the Normative Aging Study, we measured FBG, and DNA methylation of four inflammatory genes (IFN-γ, IL-6, ICAM-1, and TLR-2), up to four times between 2000 and 2011 (median = 2). We estimated short- and medium-term (1-, 7-, and 28-day preceding each clinical visit) ambient PM2.5 at each participant's address using a validated hybrid land-use regression satellite-based model. We fitted covariate-adjusted regression models accounting for repeated measures.
Mean FBG was 99.8 mg/dL (SD = 10.7), 18% of the participants had impaired fasting glucose (IFG; i.e., 100-125 mg/dL FBG) at first visit. Interquartile increases in 1-, 7-, and 28-day PM2.5 were associated with 0.57 mg/dL (95% CI: 0.02, 1.11, p = 0.04), 1.02 mg/dL (95% CI: 0.41, 1.63, p = 0.001), and 0.89 mg/dL (95% CI: 0.32, 1.47, p = 0.003) higher FBG, respectively. The same PM2.5 metrics were associated with 13% (95% CI: -3%, 33%, p = 0.12), 27% (95% CI: 6%, 52%, p = 0.01) and 32% (95% CI: 10%, 58%, p = 0.003) higher odds of IFG, respectively. PM2.5 was negatively correlated with ICAM-1 methylation (p = 0.01), but not with other genes. Mediation analysis estimated that ICAM-1 methylation mediated 9% of the association of 28-day PM2.5 with FBG.
Among nondiabetics, short- and medium-term PM2.5 were associated with higher FBG. Mediation analysis indicated that part of this association was mediated by ICAM-1 promoter methylation. Citation: Peng C, Bind MA, Colicino E, Kloog I, Byun HM, Cantone L, Trevisi L, Zhong J, Brennan K, Dereix AE, Vokonas PS, Coull BA, Schwartz JD, Baccarelli AA. 2016. Particulate air pollution and fasting blood glucose in nondiabetic individuals: associations and epigenetic mediation in the Normative Aging Study, 2000-2011. Environ Health Perspect 124:1715-1721; http://dx.doi.org/10.1289/EHP183.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background Inducible nitric oxide synthase (iNOS; encoded by nitric oxide synthase isoform 2 NOS2 ) is the major enzyme for nitric oxide synthesis in airways. As such, measurement of fractional ...concentration of exhaled nitric oxide (F eno ) provides an in vivo assessment of iNOS activity. Short-term exposure to air pollution, haplotypes, and DNA methylation in the NOS2 promoter has been associated independently with iNOS expression, F eno levels, or both. Objective We aimed to examine the effects of ambient air pollutants, NOS2 promoter haplotypes, and NOS2 promoter methylation on F eno levels in children. Methods We selected 940 participants in the Children’s Health Study who provided buccal samples and had undergone F eno measurement on the same day. DNA methylation was measured with a bisulfite-PCR Pyrosequencing assay. Seven single nucleotide polymorphisms captured the haplotype diversity in the NOS2 promoter. Average particulate matter with an aerodynamic diameter of 2.5 μm or less (PM2.5 ) and 10 μm (PM10 ) or less and ozone and nitrogen dioxide levels 7 days before F eno measurement were estimated based on air pollution data obtained at central monitoring sites. Results We found interrelated effects of PM2.5 , NOS2 promoter haplotypes, and iNOS methylation on F eno levels. Increased 7-day average PM2.5 exposure was associated with lower iNOS methylation ( P = .01). NOS2 promoter haplotypes were globally associated with NOS2 promoter methylation ( P = 6.2 × 10−8 ). There was interaction among 1 common promoter haplotype, iNOS methylation level, and PM2.5 exposure on F eno levels ( Pinteraction = .00007). Conclusion Promoter variants in NOS2 and short-term PM2.5 exposure affect iNOS methylation. This is one of the first studies showing contributions of genetic and epigenetic variations in air pollution–mediated phenotype expression.
Maternal smoking during pregnancy results in an increased risk of low birth weight through perturbations in the utero-placental exchange. Epigenetics and mitochondrial function in fetal tissues might ...be molecular signatures responsive to in utero tobacco smoke exposure.
In the framework of the ENVIRONAGE birth cohort, we investigated the effect of self-reported tobacco smoke exposure during pregnancy on birth weight and the relation with placental tissue markers such as, (1) relative mitochondrial DNA (mtDNA) content as determined by real-time quantitative PCR, (2) DNA methylation of specific loci of mtDNA (D-loop and MT-RNR1), and (3) DNA methylation of the biotransformation gene CYP1A1 (the last two determined by bisulfite-pyrosequencing). The total pregnant mother sample included 255 non-smokers, 65 former-smokers who had quit smoking before pregnancy, and 62 smokers who continued smoking during pregnancy.
Smokers delivered newborns with a birth weight on average 208 g lower 95% confidence interval (CI) -318 to -99, p = 0.0002 than mothers who did not smoke during pregnancy. In the smoker group, the relative mtDNA content was lower (-21.6%, 95% CI -35.4 to -4.9%, p = 0.01) than in the non-smoker group; whereas, absolute mtDNA methylation levels of MT-RNR1 were higher (+0.62%, 95% CI 0.21 to 1.02%, p = 0.003). Lower CpG-specific methylation of CYP1A1 in placental tissue (-4.57%, 95% CI -7.15 to -1.98%, p < 0.0001) were observed in smokers compared with non-smokers. Nevertheless, no mediation of CYP1A1 methylation nor any other investigated molecular signature was observed for the association between tobacco smoke exposure and birth weight.
mtDNA content, methylation of specific loci of mtDNA, and CYP1A1 methylation in placental tissue may serve as molecular signatures for the association between gestational tobacco smoke exposure and low birth weight.
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