scholarly journals Environmental Impact on DNA Methylation in the Germline: State of the Art and Gaps of Knowledge

2015 ◽  
Vol 2015 ◽  
pp. 1-23 ◽  
Author(s):  
Francesca Pacchierotti ◽  
Marcello Spanò
Keyword(s):  
Dna Methylation ◽  
State Of The Art ◽  
Adult Life ◽  
Human Biomonitoring ◽  
Epigenetic Mark ◽  
Cellular Phenotype ◽  
Blood Leukocytes ◽  
Daughter Cells ◽  
External Conditions ◽  
Few Data

The epigenome consists of chemical changes in DNA and chromatin that without modifying the DNA sequence modulate gene expression and cellular phenotype. The epigenome is highly plastic and reacts to changing external conditions with modifications that can be inherited to daughter cells and across generations. Whereas this innate plasticity allows for adaptation to a changing environment, it also implies the potential of epigenetic derailment leading to so-called epimutations. DNA methylation is the most studied epigenetic mark. DNA methylation changes have been associated with cancer, infertility, cardiovascular, respiratory, metabolic, immunologic, and neurodegenerative pathologies. Experiments in rodents demonstrate that exposure to a variety of chemical stressors, occurring during the prenatal or the adult life, may induce DNA methylation changes in germ cells, which may be transmitted across generations with phenotypic consequences. An increasing number of human biomonitoring studies show environmentally related DNA methylation changes mainly in blood leukocytes, whereas very few data have been so far collected on possible epigenetic changes induced in the germline, even by the analysis of easily accessible sperm. In this paper, we review the state of the art on factors impinging on DNA methylation in the germline, highlight gaps of knowledge, and propose priorities for future studies.

scholarly journals Neonatal Exposure to Estradiol/Bisphenol A Alters Promoter Methylation and Expression of Nsbp1 and Hpcal1 Genes and Transcriptional Programs of Dnmt3a/b and Mbd2/4 in the RatProstate Gland Throughout Life

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 42-55 ◽  
Author(s):  
Wan-yee Tang ◽  
Lisa M. Morey ◽  
Yuk Yin Cheung ◽  
Lynn Birch ◽  
Gail S. Prins ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bisphenol A ◽  
Early Life ◽  
Precancerous Lesions ◽  
Adult Life ◽  
Epigenetic Reprogramming ◽  
Neonatal Exposure ◽  
Epigenetic Mark ◽  
Aberrant Expression ◽  
Epigenetic Marks

Evidence supporting an early origin of prostate cancer is growing. We demonstrated previously that brief exposure of neonatal rats to estradiol or bisphenol A elevated their risk of developing precancerous lesions in the prostate upon androgen-supported treatment with estradiol as adults. Epigenetic reprogramming may be a mechanism underlying this inductive event in early life, because we observed overexpression of phosphodiesterase 4D variant 4 (Pde4d4) through induction of hypomethylation of its promoter. This epigenetic mark was invisible in early life (postnatal d 10), becoming apparent only after sexual maturation. Here, we asked whether other estrogen-reprogrammable epigenetic marks have similar or different patterns in gene methylation changes throughout life. We found that hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities. Their lifelong aberrant expression implicates them in early-life reprogramming and prostate carcinogenesis during adulthood. We speculate that the distinctly different fate of early-life epigenetic marks during adulthood reflects the complex nature of lifelong editing of early-life epigenetic reprogramming.

scholarly journals Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Pinpin Long ◽  
Qiuhong Wang ◽  
Yizhi Zhang ◽  
Xiaoyan Zhu ◽  
Kuai Yu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Coronary Syndrome ◽  
Methylation Level ◽  
Meta Analysis ◽  
Regulation Of Gene Expression ◽  
Density Lipoprotein ◽  
Blood Leukocytes ◽  
Coronary Syndrome ◽  
A Genome ◽  
Increased Risk

Abstract Background Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. Methods We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. Results We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02–1.48; P = 0.03). Conclusions We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

scholarly journals Blood-Based Detection of Colorectal Cancer Using Cancer-Specific DNA Methylation Markers

Diagnostics ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 51
Author(s):  
Nam-Yun Cho ◽  
Ji-Won Park ◽  
Xianyu Wen ◽  
Yun-Joo Shin ◽  
Jun-Kyu Kang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Sensitivity And Specificity ◽  
Stage Iv ◽  
High Sensitivity ◽  
Liquid Biopsies ◽  
Blood Leukocytes ◽  
Marker Panel ◽  
A Genome ◽  
Methylight Assay

Cancer tissues have characteristic DNA methylation profiles compared with their corresponding normal tissues that can be utilized for cancer diagnosis with liquid biopsy. Using a genome-scale DNA methylation approach, we sought to identify a panel of DNA methylation markers specific for cell-free DNA (cfDNA) from patients with colorectal cancer (CRC). By comparing DNA methylomes between CRC and normal mucosal tissues or blood leukocytes, we identified eight cancer-specific methylated loci (ADGRB1, ANKRD13, FAM123A, GLI3, PCDHG, PPP1R16B, SLIT3, and TMEM90B) and developed a five-marker panel (FAM123A, GLI3, PPP1R16B, SLIT3, and TMEM90B) that detected CRC in liquid biopsies with a high sensitivity and specificity with a droplet digital MethyLight assay. In a set of cfDNA samples from CRC patients (n = 117) and healthy volunteers (n = 60), a panel of five markers on the platform of the droplet digital MethyLight assay detected stages I–III and stage IV CRCs with sensitivities of 45.9% and 95.7%, respectively, and a specificity of 95.0%. The number of detected markers was correlated with the cancer stage, perineural invasion, lymphatic emboli, and venous invasion. Our five-marker panel with the droplet digital MethyLight assay showed a high sensitivity and specificity for the detection of CRC with cfDNA samples from patients with metastatic CRC.

Abstract 15: Glucose-Mediated Remodeling of Cardiac DNA Methylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Mark E Pepin ◽  
David K Crossman ◽  
Joseph P Barchue ◽  
Salpy V Pamboukian ◽  
Steven M Pogwizd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Dna Methylation ◽  
Diabetic Cardiomyopathy ◽  
Left Ventricular ◽  
Epigenetic Mark ◽  
Gene Transcript ◽  
Transcript Levels ◽  
Glycemic Memory

To identify the role of glucose in the development of diabetic cardiomyopathy, we had directly assessed glucose delivery to the intact heart on alterations of DNA methylation and gene expression using both an inducible heart-specific transgene (glucose transporter 4; mG4H) and streptozotocin-induced diabetes (STZ) mouse models. We aimed to determine whether long-lasting diabetic complications arise from prior transient exposure to hyperglycemia via a process termed “glycemic memory.” We had identified DNA methylation changes associated with significant gene expression regulation. Comparing our results from STZ, mG4H, and the modifications which persist following transgene silencing, we now provide evidence for cardiac DNA methylation as a persistent epigenetic mark contributing to glycemic memory. To begin to determine which changes contribute to human heart failure, we measured both RNA transcript levels and whole-genome DNA methylation in heart failure biopsy samples (n = 12) from male patients collected at left ventricular assist device placement using RNA-sequencing and Methylation450 assay, respectively. We hypothesized that epigenetic changes such as DNA methylation distinguish between heart failure etiologies. Our findings demonstrated that type 2 diabetic heart failure patients (n = 6) had an overall signature of hypomethylation, whereas patients listed as ischemic (n = 5) had a distinct hypermethylation signature for regulated transcripts. The focus of this initial analysis was on promoter-associated CpG islands with inverse changes in gene transcript levels, from which diabetes (14 genes; e.g. IGFBP4) and ischemic (12 genes; e.g. PFKFB3) specific targets emerged with significant regulation of both measures. By combining our mouse and human molecular analyses, we provide evidence that diabetes mellitus governs direct regulation of cellular function by DNA methylation and the corresponding gene expression in diabetic mouse and human hearts. Importantly, many of the changes seen in either mouse type 1 diabetes or human type 2 diabetes were similar supporting a consistent mechanism of regulation. These studies are some of the first steps at defining mechanisms of epigenetic regulation in diabetic cardiomyopathy.

scholarly journals ANALYSIS OF THE ASSOCIATION OF THE METHYLATION LEVELS OF MIR10B AND MIR21 GENES IN BLOOD LEUKOCYTES WITH ADVANCED CAROTID ATHEROSCLEROSIS

2018 ◽  
Vol 33 (2) ◽  
pp. 77-82
Author(s):  
Iu. A. Koroleva ◽  
A. A. Zarubin ◽  
A. V. Markov ◽  
A. N. Kazancev ◽  
O. L. Barbarash ◽  
...  
Keyword(s):  
Risk Factors ◽  
Dna Methylation ◽  
Methylation Level ◽  
Carotid Atherosclerosis ◽  
Gene Promoter ◽  
Control Group ◽  
Coding Region ◽  
Blood Leukocytes ◽  
Atherosclerosis Risk Factors

Complications of atherosclerosis remain the leading cause of morbidity and mortality worldwide. MiRNAs are short regulatory molecules that are involved in all processes of pathogenesis. Expression of miRNAs is regulated by DNA methylation. Methylation and/or expression of MIR10B and MIR21 genes are known to vary in atherosclerotic tissues of the arteries, but there is no data about the changes in the methylation levels of these genes in blood leukocytes and their association with atherosclerosis risk factors.Objective.To evaluate the association of methylation levels of MIR10B and MIR21 genes in the blood leukocytes with risk factors and pathogenetically significant traits of carotid atherosclerosis.Material and Methods. DNA for the study was extracted from the samples of blood leukocytes of 122 patients with advanced carotid atherosclerosis as well as from blood leukocytes of 135 individuals in the control group. The DNA methylation level was analyzed by bisulfite pyrosequencing.Results.The methylation level of the MIR10B and MIR21 genes in leukocytes of patients with atherosclerosis is higher than in the leukocytes of the control group. In leukocytes of patients with carotid atherosclerosis the methylation level of the MIR21 gene promoter was correlated with type 2 diabetes and serum cholesterol level, and the methylation level of the coding region of the MIR10B gene was correlated with smoking.Conclusions.The level of DNA methylation in the regions of MIR10B and MIR21 genes in blood leukocytes is associated with the risk of advanced atherosclerosis of the carotid arteries. 

DNA methylation versus gene expression

Development ◽  
1984 ◽  
Vol 83 (Supplement) ◽  
pp. 31-40
Author(s):  
Adrian P. Bird
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Division ◽  
Methylation Pattern ◽  
Current Evidence ◽  
Evolutionary Perspective ◽  
Cell Type ◽  
Versus Gene ◽  
Daughter Cells ◽  
The Relationship

Vertebrate DNA is methylated at a high proportion of cytosine residues in the sequence CpG, and it has been suggested that the distribution of methylated and non-methylated CpGs in a given cell type influences the pattern of gene expression in those cells. Since a DNA methylation pattern is normally transmitted faithfully to daughter cells via cell division, this idea suggests an origin for stable, clonally inherited patterns of gene expression. This article discusses some of the current evidence for a relationship between DNA methylation and gene expression. Although the evidence is incomplete, it appears already that the relationship is variable: transcription of some genes is repressed by the presence of 5-methylcytosine at certain CpGs, and may be controlled by methylation, while transcription of other genes is indifferent to methylation. In attempting to explain this variability it is helpful to adopt an evolutionary perspective.

Abstract P133: Epigenome-Wide Association Study of Moderate-Vigorous Physical Activity in Adult African Americans Identifies Loci Near HCCA2

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Steven Nguyen ◽  
Weihua Guan ◽  
Chong Wu ◽  
Megan Grove ◽  
Rui Xia ◽  
...  
Keyword(s):  
Physical Activity ◽  
Dna Methylation ◽  
Leisure Time ◽  
Acute Exercise ◽  
Association Studies ◽  
Vigorous Physical Activity ◽  
Genomic Region ◽  
Epigenetic Mark ◽  
Global Methylation ◽  
Exercise Interventions

Regular moderate-vigorous physical activity (MVPA) reduces the risk of cardiovascular and other chronic diseases, among other important benefits at all life stages. It is hypothesized that physical activity may alter disease risk via epigenetic modifications, including potentially long-standing changes in DNA methylation as previous research has shown epigenetic changes following exercise interventions. Most existing reports examine global methylation or study acute exercise effects on DNA methylation. To our knowledge, there are no published epigenome-wide association studies (EWAS) of habitual MVPA. In this analysis, we tested associations between leisure time MVPA and genome-wide variation in CpG methylation, an epigenetic mark, in 2,601 African American participants (1,663 women; mean age 56.6 years) in the Atherosclerosis Risk in Communities (ARIC) study. The Illumina HM450K Bead Chip was used to measure methylation in 471,035 CpG sites in stored frozen leukocyte samples, from visit 2 (1990-1992) or 3 (1993-1995). Linear regression models tested the cross-sectional association of DNA methylation M-value with self-reported leisure time MVPA at the visit of sample collection, modeled as minutes of MVPA per week and by category based on the AHA guidelines for physical activity in adults (none, less than 150, or at least 150 minutes MVPA per week), adjusting for age, sex, body mass index, education, alcohol use in grams per week, smoking status, cancer status, white blood cell count, imputed cell-type proportions using the Houseman method, and batch effects with the top 30 HM450K built-in nonnegative control probe principal components. Three CpGs, cg08269485, cg20272155, and cg08966208, upstream of the cathepsin D encoding gene, CTSD, were observed to be significantly inversely associated (q<0.05, FDR) with MVPA minutes/week. This is a strongly imprinted genomic region (chr11p15.5) and the region has also been reported to include DNA methylation variants that changed in response to an exercise training intervention. Additionally, 163 CpGs that we identified in the literature to be associated with habitual MVPA were also tested using the same models. One CpG, cg07863043, upstream of the adenomatosis polyposis coli gene, APC, in the 5q22.2 genomic region, was observed to be significantly positively associated with achieving at least 150 minutes of MVPA per week compared to none (q=0.0001, FDR). APC encodes a tumor suppressor protein that is an antagonist of the Wnt signaling pathway, and is involved in carcinogenesis and embryonic development. Replication in other populations is ongoing to confirm these findings as well as to identify additional physical activity-related DNA methylation variants.

Abstract 24: Prenatal Socioeconomic Position is Associated with Adipose Tissue DNA Methylation in Women and Not Men

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Golareh Agha ◽  
Andres E Houseman ◽  
Karl T Kelsey ◽  
Charles B Eaton ◽  
Stephen L Buka ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
New England ◽  
Early Life ◽  
Blood Leukocytes ◽  
Early Life Adversity ◽  
Smoking During Pregnancy ◽  
Socioeconomic Index ◽  
Affected Tissue ◽  
Subcutaneous Adipose

RATIONALE: Adiposity is a major cardiovascular risk factor, suggesting an important role for adipose tissue in development of cardiovascular outcomes. There is evidence that early life adversity has a lasting impact on the development of adiposity, particularly in women. In utero exposure to famine was related to adulthood adiposity in women but not men, and associations between early life socioeconomic adversity and adulthood adiposity is established in women but less so in men. There is interest in epigenetic mechanisms by which early life adversity may program risk for adiposity, and utilizing directly affected tissue such as adipose tissue is ideal for investigating such mechanisms. Objective: To determine whether prenatally-assessed socioeconomic index (SEI) is associated with adulthood genome-wide DNA methylation in blood and adipose tissue, and whether associations differ between men and women. Methods: Participants (aged 44-50 y) were from the New England Family Study birth cohort, born in Providence, RI. Of 400 participants assessed during 2010-2011, a representative subsample of 106 participants (68 women, 38 men) was selected for DNA methylation analyses. SEI was measured prenatally as a composite numerical score, using a weighted percentile of both parents’ educational attainment, occupation, and income relative to the US population. DNA methylation in subcutaneous adipose tissue and peripheral blood leukocytes was evaluated using the Infinium HumanMethylation450K BeadChip. Results: Prenatal SEI was associated with adipose tissue DNA methylation in women (permutation-based omnibus p-values <0.001), but not men or the pooled sample. Associations in women were not attenuated after adjustment for race, current smoking, or mother’s smoking during pregnancy. Prenatal SEI was not related to blood DNA methylation. Conclusion: Results provide mechanistic insight on the association between early life adversity and adulthood adiposity, which is seen mainly in women.

Reproducibility-optimized detection of differential DNA methylation

Epigenomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 747-755
Author(s):  
Veronika Suni ◽  
Fatemeh Seyednasrollah ◽  
Bishwa Ghimire ◽  
Sini Junttila ◽  
Asta Laiho ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Throughput Sequencing ◽  
State Of The Art ◽  
Methylation Status ◽  
Real Data ◽  
Epigenetic Mechanism ◽  
Methylation Analysis ◽  
Test Statistic ◽  
Differentially Methylated Regions ◽  
Dna Methylation Analysis

Aim: DNA methylation is a key epigenetic mechanism regulating gene expression. Identifying differentially methylated regions is integral to DNA methylation analysis and there is a need for robust tools reliably detecting regions with significant differences in their methylation status. Materials & methods: We present here a reproducibility-optimized test statistic (ROTS) for detection of differential DNA methylation from high-throughput sequencing or array-based data. Results: Using both simulated and real data, we demonstrate the ability of ROTS to identify differential methylation between sample groups. Conclusion: Compared with state-of-the-art methods, ROTS shows competitive sensitivity and specificity in detecting consistently differentially methylated regions.

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