DNA isolation method is a source of global DNA methylation variability measured with LUMA. Experimental analysis and a systematic review.
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ABSTRACT:
SUBMITTER: Soriano-Tarraga C
PROVIDER: S-EPMC3621987 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Our purpose was to identify epigenetic markers of breast cancer risk, which can be reliably measured in peripheral blood and are amenable for large population screening. We used 2 independent assays, luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) to measure "global methylation content" in peripheral blood DNA from a well-characterized population-based case-control study. We examined associations between methylation levels and breast cancer risk among 1055 cases and 1101 controls and potential influences of 1-carbon metabolism on global methylation. Compared with women in the lowest quintile of LUMA methylation, those in the highest quintile had a 2.41-fold increased risk of breast cancer (95% confidence interval: 1.83-3.16; P, trend<0.0001). The association did not vary by other key tumor characteristics and lifestyle risk factors. Consistent with LUMA findings, genome-wide methylation profiling of a subset of samples revealed greater promoter hypermethylation in breast cancer case participants (P=0.04); higher LUMA was associated with higher promoter methylation in the controls (P=0.05). LUMA levels were also associated with functional sodium nitroprusside in key 1-carbon metabolizing genes, MTHFR C677T (P=0.001) and MTRR A66G (P=0.018). LINE-1 methylation was associated with neither breast cancer risk nor 1-carbon metabolism. Our results show that global promoter hypermethylation measured in peripheral blood was associated with breast cancer risk.
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Project description:BackgroundGlobal hypomethylation has been suggested to cause genomic instability and lead to an increased risk of cancer. We examined the association between the global methylation level of peripheral blood leukocyte DNA and breast cancer among Japanese women.MethodsWe conducted a hospital-based case-control study of 384 patients aged 20-74 years with newly diagnosed, histologically confirmed invasive breast cancer, and 384 matched controls from medical checkup examinees in Nagano, Japan. Global methylation levels in leukocyte DNA were measured by LUminometric Methylation Assay. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between global hypomethylation and breast cancer were estimated using a logistic regression model.ResultsCompared with women in the highest tertile of global methylation level, ORs for the second and lowest tertiles were 1.87 (95% CI=1.20-2.91) and 2.86 (95% CI=1.85-4.44), respectively. Global methylation levels were significantly lower in cases than controls, regardless of the hormone receptor status of the cancer (all P values for trend <0.05).InterpretationThese findings suggest that the global methylation level of peripheral blood leukocyte DNA is low in patients with breast cancer and may be a potential biomarker for breast cancer risk.
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Project description:Interindividual variability of DNA methylation is a mechanism of the epigenetic drift in aging. Studies on cross-sectional data have discovered a change in methylation variability in association with age. However, thus far, no method explored DNA methylation variability in longitudinal data, which was the aim of this study. First, we performed a simulation study to explore methods for estimating methylation variability in longitudinal data. Second, an epigenome-wide association study (EWAS) on 1011 longitudinal samples (385 individuals followed up to 18 years) was performed to identify age-varying methylation sites using these methods. Following Breusch-Pagan test of heteroscedasticity, we showed that a linear regression model, where the residuals were used in a mixed effect model with a random intercept, properly estimated the change of interindividual variability over time. Our EWAS identified 570 CpG sites where methylation variability was significantly associated with age (P < 1.3 × 10-7). Gene regions of identified loci were enriched in nervous system development functions. In conclusion, we provide a method for analyzing methylation variability in longitudinal data and further identified age-varying methylation loci in a longitudinal analysis using these methods.
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Project description:DNA methylation provides a pivotal layer of epigenetic regulation in eukaryotes that has significant involvement for numerous biological processes in health and disease. The function of methylation of cytosine bases in DNA was originally proposed as a "silencing" epigenetic marker and focused on promoter regions of genes for decades. Improved technologies and accumulating studies have been extending our understanding of the roles of DNA methylation to various genomic contexts including gene bodies, repeat sequences and transcriptional start sites. The demand for comprehensively describing DNA methylation patterns spawns a diversity of DNA methylation profiling technologies that target its genomic distribution. These approaches have enabled the measurement of cytosine methylation from specific loci at restricted regions to single-base-pair resolution on a genome-scale level. In this review, we discuss the different DNA methylation analysis technologies primarily based on the initial treatments of DNA samples: bisulfite conversion, endonuclease digestion and affinity enrichment, involving methodology evolution, principles, applications, and their relative merits. This review may offer referable information for the selection of various platforms for genome-wide analysis of DNA methylation.
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Project description:DNA methylation plays a critical role in brain aging and Alzheimer's disease (AD). While prior studies have largely focused on testing mean DNA methylation, DNA methylation instability (quantified by DNA methylation variability) may also affect disease susceptibility. Using DNA methylation data collected by the Religious Orders Study and the Rush Memory and Aging Project, we identified 249 and 115 variably methylated probes (VMPs) associated with amyloid-? and neurofibrillary tangles, respectively. These VMPs clustered into 133 and 14 regions, respectively. Notably, we found that most of these VMPs did not overlap with differentially methylated probes, indicating that VMPs and differentially methylated probes may capture different sets of genes associated with AD pathology. Overall, our results demonstrated that DNA methylation instability affects AD neuropathology and highlights the importance of testing methylation variability in epigenetic research.
| S-EPMC6436841 | biostudies-literature
Project description:AimWe examined maternal prepregnancy anthropometry and cord blood DNA methylation.MethodsAssociations between maternal measures (i.e., weight, height, waist circumference, hip circumference, skinfolds, leptin) and methylation β-values at each CpG (measured by the Infinium MethylationEPIC BeadChip) were estimated among 391 singletons.ResultsTotal of 18% of mothers were obese (body mass index ≥ 30) and 27% centrally obese (waist-to-hip ratio ≥ 0.85). One Bonferroni significant CpG with respect to obesity (cg02975187) and two with central obesity (cg12053563, cg12549355) were identified (p < 6 × 10-8). A suggestive association (p < 10-6) was observed at SFRS8 with increasing body mass index. SFRS8 was previously identified with propensity for weight gain in adults.ConclusionWhile associations identified with multiple measures related to maternal adiposity suggest different pathways, methylation differences were small in magnitude.
| S-EPMC6371845 | biostudies-literature
Project description:Introduction/purposeLimited studies have examined the association of physical activity with reproductive hormones, DNA methylation, and pubertal status among adolescents.MethodsAmong 248 boys and 271 girls, we estimated daily physical activity levels based on 7 d of wrist-worn accelerometer data. We used an isotemporal substitution paradigm and sex-stratified regression models to examine the association of physical activity levels with 1) testosterone, cortisol, progesterone, and androstenedione concentrations; 2) DNA methylation of long interspersed nucleotide (LINE-1) repeats and the genes H19, hydroxysteroid (11-Beta) dehydrogenase 2 (HSD11B2), and peroxisome proliferator-activated receptor alpha (PPARA) from blood leukocytes; and 3) Tanner stages, adjusted for age, BMI, and socioeconomic status.ResultsIn boys, substituting 30 min of moderate physical activity for 30 min of sedentary behavior per day was associated with 29% (-49%, 0%) of lower testosterone and 29% (4%, 61%) of higher progesterone. Substituting 30 min of light physical activity for sedentary behavior was associated with 13% (-22%, -2%) of lower progesterone. Among girls, 30 min of additional sedentary behavior was associated with 8% (-15%, 0%) of lower testosterone and 24% (8%, 42%) of higher progesterone concentrations. Substituting 30 min of moderate physical activity for sedentary behavior was associated with 15% (0%, 31%) of higher cortisol, whereas substituting the same amount of light physical activity for sedentary behavior was associated with 22% (-39%, 0%) of lower progesterone. Substituting 30 min of vigorous physical activity for sedentary behavior per day was associated with almost six times higher levels (5.83, 95% confidence interval = 1.79-9.86) of HSD11B2 methylation in boys.ConclusionsAccelerometer-measured daily physical activity was associated with reproductive hormones and HSD11B2 DNA methylation, differed by sex and activity intensity levels.
| S-EPMC7024035 | biostudies-literature
Project description:PURPOSE: Methylation of sperm DNA is impaired in many infertile men potentially adversely effecting reproductive outcomes. In somatic cells oxidative damage to DNA and hyperhomocysteinaemia are linked with DNA hypomethylation. The objective of this study was to investigate if these pathologies also impair sperm DNA methylation. METHODS: The relationship between sperm DNA quality, oxidative stress and serum homocysteine was analysed at study entry and after 3 months of antioxidant treatment. RESULTS: Overall a significant negative correlation was observed between sperm DNA methylation and sperm DNA fragmentation, as well as seminal reactive oxygen species (ROS) production. Sperm DNA methylation was not significantly related to serum homocysteine concentrations. Administration of an antioxidant supplement produced a significant fall in seminal ROS levels and sperm DNA fragmentation, while increasing sperm DNA methylation. CONCLUSIONS: These results suggest that oxidative stress related damage to sperm DNA impedes the process of methylation, while antioxidant supplementation appears to have the potential to reduce DNA damage and normalize sperm DNA methylation.
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Project description:Ischemic stroke (IS), a heterogeneous multifactorial disorder, is among the leading causes of mortality and long-term disability in the western world. Epidemiological data provides evidence for a genetic component to the disease, but its epigenetic involvement is still largely unknown. Epigenetic mechanisms, such as DNA methylation, change over time and may be associated with aging processes and with modulation of the risk of various pathologies, such as cardiovascular disease and stroke. We analyzed 2 independent cohorts of IS patients. Global DNA methylation was measured by luminometric methylation assay (LUMA) of DNA blood samples. Univariate and multivariate regression analyses were used to assess the methylation differences between the 3 most common IS subtypes, large-artery atherosclerosis (LAA), small-artery disease (SAD), and cardio-aortic embolism (CE). A total of 485 IS patients from 2 independent hospital cohorts (n?=?281 and n?=?204) were included, distributed across 3 IS subtypes: LAA (78/281, 59/204), SAD (97/281, 53/204), and CE (106/281, 89/204). In univariate analyses, no statistical differences in LUMA levels were observed between the 3 etiologies in either cohort. Multivariate analysis, adjusted by age, sex, hyperlipidemia, and smoking habit, confirmed the lack of differences in methylation levels between the analyzed IS subtypes in both cohorts. Despite differences in pathogenesis, our results showed no global methylation differences between LAA, SAD, and CE subtypes of IS. Further work is required to establish whether the epigenetic mechanism of methylation might play a role in this complex disease.
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Project description:Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced lag between the copying of genetic and epigenetic information in embryonic stem cells that is reconsolidated within hours to accomplish faithful mitotic transmission. Populations of arrested cells show a global reduction of lag-induced intermediate CpG methylation when compared to proliferating cells, whereas sites of transcription factor engagement appear cell-cycle invariant. Alternatively, the cancer cell line HCT116 preserves global epigenetic heterogeneity independently of cell-cycle arrest. Taken together, our data suggest that heterogeneous methylation largely reflects asynchronous proliferation, but is intrinsic to actively engaged cis-regulatory elements and cancer.
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