scholarly journals Intensity-Specific Differential Leukocyte DNA Methylation in Physical (In)Activity: An Exploratory Approach

2018 ◽  
Vol 21 (2) ◽  
pp. 101-111 ◽  
Author(s):  
Maarten Caspers ◽  
Sara Blocquiaux ◽  
Ruben Charlier ◽  
Sara Knaeps ◽  
Johan Lefevre ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Correlation Coefficients ◽  
Global Dna Methylation ◽  
Site Specific ◽  
Cpg Sites ◽  
Cpg Site ◽  
Biological Pathway Analysis ◽  
Exploratory Approach ◽  
Health Related ◽  
Related Pathway

The aim of this exploratory study was to investigate how sedentary behavior (SB) and physical activity (PA) influence DNA methylation at a global, gene-specific, and health-related pathway level. SB, light PA (LPA), and moderate-to-vigorous PA (MVPA) were assessed objectively for 41 Flemish men using the SenseWear Pro 3 Armband. CpG site-specific methylation in leukocytes was determined using the Illumina HumanMethylation 450 BeadChip. Correlations were calculated between time spent on the three PA intensity levels and global DNA methylation, using a z-score-based method to determine global DNA methylation levels. To determine whether CpG site-specific methylation can be predicted by these three PA intensity levels, linear regression analyses were performed. Based on the significantly associated CpG sites at α = 0.005, lists were created including all genes with a promoter region overlapping these CpG sites. A biological pathway analysis determined to what extent these genes are overrepresented within several pathways. No significant associations were observed between global DNA methylation and SB (r = 0.084), LPA (r = -0.168), or MVPA (r = -0.125), although the direction of the correlation coefficients is opposite to what is generally reported in literature. SB has a different impact on global and gene-specific methylation than PA, but also LPA and MVPA affect separate genes and pathways. Furthermore, the function of a pathway seems to determine its association with SB, LPA, or MVPA. Multiple PA intensity levels, including SB, should be taken into account in future studies investigating the effect of physical (in)activity on human health through epigenetic mechanisms.

Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level

2015 ◽  
Vol 129 (4) ◽  
pp. 385-394 ◽  
Author(s):  
Xuemei Xie ◽  
Hongjie Gao ◽  
Wanjiang Zeng ◽  
Suhua Chen ◽  
Ling Feng ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gestational Diabetes ◽  
Glucose Level ◽  
Peroxisome Proliferator ◽  
Diabetes Group ◽  
Peroxisome Proliferator Activated Receptor ◽  
Site Specific ◽  
Cpg Site

Among all the participants, the maternal gestational glucose level was positively correlated with placental DNA methylation. The correlation between gestational 2-h post-OGTT glycaemia and CpG site-specific methylation in placenta was stronger in the gestational diabetes group.

scholarly journals DNA methylation partially mediates the relationship between childhood adversity and depressive symptoms in adolescence

2021 ◽  
Author(s):  
Brooke J. Smith ◽  
Alexandre A Lussier ◽  
Janine Cerutti ◽  
Daniel J. Schaid ◽  
Andrew J. Simpkin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Depressive Symptoms ◽  
Life Course ◽  
Adolescent Depression ◽  
Childhood Adversity ◽  
Depression Symptoms ◽  
Cpg Sites ◽  
Cpg Site ◽  
Sensitive Periods ◽  
The Relationship

Background: Exposure to adversity during childhood is estimated to at least double the risk of depression later in life. Some evidence suggests childhood adversity may have a greater impact on depression risk, if experienced during specific windows of development called sensitive periods. During these sensitive periods, there is evidence that adversity may leave behind biological memories, including changes in DNA methylation (DNAm). Here we ask if those changes play a role in the link between adversity and later adolescent depressive symptoms. Methods: We applied a method for high-dimensional mediation analysis using data from a subsample (n=627-675) of the Avon Longitudinal Study of Parents and Children. We first assessed the possibility of time-dependent relationships between seven types of childhood adversity (caregiver abuse, physical/sexual abuse, maternal psychopathology, one-adult household, family instability, financial stress, neighborhood disadvantage), measured on at least four occasions between ages 0-7 years, and adolescent depression at mean age 10.6. Specifically, we considered three types of life course hypotheses (sensitive periods, accumulation, and recency), and then evaluated which of these hypotheses had the strongest association in each adversity-adolescent depression relationship using the structured life course modeling approach (SLCMA; pronounced slick-mah). To conduct the mediation analyses, we used a combination of pruning and sure independence screening (a dimension reduction method) to reduce the number of methylated CpG sites under consideration to a viable subset for our sample size. We then applied a sparse group lasso penalized model to identify the top mediating loci from that subset using the combined strength of the coefficient measuring the relationship between the childhood adversity and a CpG site (α) and of the coefficient measuring the relationship between the CpG site and depressive symptoms (β) as a metric. Using a Monte Carlo method for assessing mediation (MCMAM), we assigned a significance level and confidence interval to each identified mediator. Results: Across all seven adversities, we identified a total of 70 CpG sites that showed evidence of mediating the relationship between adversity and adolescent depression symptoms. Of these 70 mediators, 37 were significant at the p < 0.05 level when applying the MCMAM, a method tailored to estimating the significance of SEM-derived mediation effects. These sites exhibited four different mediating patterns, differentiated by the direction of α and β. These patterns had signals that were: (1) both positive (19 loci), (2) both negative (18 loci), (3) positive α and negative β (23 loci) or (4) negative α and positive β (10 loci). Conclusion: Our results suggest that DNAm partially mediates the relationship between different types of childhood adversity and depressive symptoms in adolescence. These findings provide insight into the biological mechanisms that link childhood adversity to depression, which will ultimately help develop treatments to prevent depression in more vulnerable populations.

scholarly journals Consistency and Variability of DNA Methylation in Women During Puberty, Young Adulthood, and Pregnancy

2017 ◽  
Vol 9 ◽  
pp. 1179237X1772154 ◽  
Author(s):  
Su Chen ◽  
Nandini Mukherjee ◽  
Vimala Devi Janjanam ◽  
S Hasan Arshad ◽  
Ramesh J Kurukulaaratchy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Pregnancy ◽  
Mixed Models ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Late Pregnancy ◽  
Functional Enrichment ◽  
Cell Type ◽  
Intraclass Correlation Coefficients ◽  
Cpg Sites

Prior DNA methylation (DNA-m) analyses have identified cytosine-phosphate-guanine (CpG) sites, which show either a significant change or consistency during lifetime. However, the proportion of CpGs that are neither significantly different nor consistent over time (indifferent CpGs) is unknown. We investigated the methylation dynamics, both longitudinal changes and consistency, in women from preadolescence to late pregnancy using DNA-m of peripheral blood cells. Consistency of cell type–adjusted DNA-m between paired individuals was assessed by regressing CpGs of subsequent age on the prior, stability by intraclass correlation coefficients (>0.5), and changes by linear mixed models. In the first 2 transitions (10-18 years and 18 years to early pregnancy), 19.5% and 20.9% CpGs were consistent, but only 0.35% in the third transition (from early to late pregnancy). Significant changes in methylation were found in 0.7%, 5.6%, and 0% CpGs, respectively. Functional enrichment analyses of genes with significant changes in DNA-m in early pregnancy (5.6%) showed that the maternal DNA-m seems to reflect signaling pathways between the uterus and the trophoblast. The transition from early to late pregnancy showed low consistency/stability and no changes, suggesting the presence of a large proportion of indifferent CpGs in late pregnancy.

scholarly journals Correlation of Infinium HumanMethylation450K and MethylationEPIC BeadChip arrays in cartilage

2019 ◽  
Author(s):  
Kathleen Cheung ◽  
Marjolein J. Burgers ◽  
David A. Young ◽  
Simon Cockell ◽  
Louise N. Reynard
Keyword(s):  
Dna Methylation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Pearson Correlation ◽  
Cell Types ◽  
Poor Correlation ◽  
450K Array ◽  
Human Cartilage ◽  
Cpg Sites ◽  
Cpg Site

AbstractBackgroundDNA methylation of CpG sites is commonly measured using Illumina Infinium BeadChip platforms. The Infinium MethylationEPIC array has replaced the Infinium Methylation450K array. The two arrays use the same technology, with the EPIC array assaying 865859 CpG sites, almost double the number of sites present on the 450K array. In this study, we compare DNA methylation values of shared CpGs of the same human cartilage samples assayed using both platforms.MethodsDNA methylation was measured in 21 human cartilage samples using the Illumina Infinium Methylation450K BeadChip and the Infinium methylationEPIC array. Additional matched 450K and EPIC data in whole tumour and whole blood were downloaded from GEO GSE92580 and GSE86833 respectively. Data were processed using the Bioconductor package Minfi. Additionally, DNA methylation of six CpG sites was validated for the same 21 cartilage samples by use of pyrosequencing.ResultsIn cartilage samples, overall sample correlations between methylation values generated by the two arrays were high (Pearson correlation coefficient r > 0.96). However, 50.5% of CpG sites showed poor correlation (r < 0.2) between arrays. Sites with limited variance and with either very high or very low methylation levels in cartilage exhibited lower correlation values, corroborating prior studies in whole blood. Bisulfite pyrosequencing did not highlight one array as generating more accurate methylation values that the other. For a specific CpG site, the array methylation correlation coefficient differed between cartilage, tumour and whole blood, reflecting the difference in methylation variance between cell types. These patterns can be observed across different tissues with different CpG site variances. When performing differential methylation analysis, the mean probe correlation co-efficient increased with increasing Δβ threshold used.ConclusionCpG sites with low variability within a tissue showed poor reproducibility between arrays. However, variance and thus reproducibility differs across different tissue types. Therefore, researchers should be cautious when analysing methylation of CpG sites that show low methylation variance within the cell type of interest, regardless of platform or method used to assay methylation.

scholarly journals Epigenetic Reprogramming of Immune Cells in Women With PCOS Impact Genes Controlling Reproductive Function

2019 ◽  
Vol 104 (12) ◽  
pp. 6155-6170 ◽  
Author(s):  
Danielle Hiam ◽  
David Simar ◽  
Rhianna Laker ◽  
Ali Altıntaş ◽  
Melanie Gibson-Helm ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
T Helper Cells ◽  
Reproductive Function ◽  
Global Dna Methylation ◽  
T Helper ◽  
Cpg Sites ◽  
Helper Cells ◽  
Genome Wide ◽  
A Cell

Abstract Context Polycystic ovary syndrome (PCOS) is a chronic disease affecting reproductive function and whole-body metabolism. Although the etiology is unclear, emerging evidence indicates that the epigenetics may be a contributing factor. Objective To determine the role of global and genome-wide epigenetic modifications in specific immune cells in PCOS compared with controls and whether these could be related to clinical features of PCOS. Design Cross-sectional study. Participants Women with (n = 17) or without PCOS (n = 17). Setting Recruited from the general community. Main Outcome Measures Isolated peripheral blood mononuclear cells were analyzed using multicolor flow cytometry methods to determine global DNA methylation levels in a cell-specific fashion. Transcriptomic and genome-wide DNA methylation analyses were performed on T helper cells using RNA sequencing and reduced representation bisulfite sequencing. Results Women with PCOS had lower global DNA methylation in monocytes (P = 0.006) and in T helper (P = 0.004), T cytotoxic (P = 0.004), and B cells (P = 0.03). Specific genome-wide DNA methylation analysis of T helper cells from women with PCOS identified 5581 differentially methylated CpG sites. Functional gene ontology enrichment analysis showed that genes located at the proximity of differentially methylated CpG sites belong to pathways related to reproductive function and immune cell function. However, these genes were not altered at the transcriptomic level. Conclusions It was shown that PCOS is associated with global and gene-specific DNA methylation remodeling in a cell type–specific manner. Further investigation is warranted to determine whether epigenetic reprogramming of immune cells is important in determining the different phenotypes of PCOS.

scholarly journals Prenatal exposure to tobacco smoke sex dependently influences methylation and mRNA levels of the Igf axis in lungs of mouse offspring

2017 ◽  
Vol 312 (4) ◽  
pp. L542-L555 ◽  
Author(s):  
K. F. Meyer ◽  
S. Krauss-Etschmann ◽  
W. Kooistra ◽  
M. Reinders-Luinge ◽  
W. Timens ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Body Weight ◽  
Prenatal Exposure ◽  
Promoter Methylation ◽  
Lung Development ◽  
Smoke Exposure ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Site Specific ◽  
Cpg Site

Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and chronic obstructive pulmonary disease (COPD). Birth cohort studies show genome-wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns of Igf1 and Igf1r, thus influencing transcriptional activity and contributing to abnormal lung development. We measured and compared mRNA levels along with promoter methylation of Igf1 and Igf1r and their protein concentrations in lung tissue of 30-day-old mice that had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Female PSE mice showed lower mRNA levels of Igf1 and its receptor ( Igf1: P = 0.05; Igf1r: P = 0.03). Furthermore, CpG-site-specific methylation changes were detected in Igf1r in a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Prenatal exposure to smoke induces a CpG-site-specific loss of Igf1r promoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation and Igf1 and Igf1r mRNA levels. The observations support a role for Igf1 and Igf1r in abnormal development.

scholarly journals Correlation Patterns Between DNA Methylation and Gene Expression in The Cancer Genome Atlas

2019 ◽  
Vol 18 ◽  
pp. 117693511982877 ◽  
Author(s):  
John CG Spainhour ◽  
Hong Seo Lim ◽  
Soojin V Yi ◽  
Peng Qiu
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Region ◽  
The Cancer Genome Atlas ◽  
Gene Body ◽  
Cpg Sites ◽  
Cpg Site ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: DNA methylation is a form of epigenetic modification that has been shown to play a significant role in gene regulation. In cancer, DNA methylation plays an important role by regulating the expression of oncogenes. The role of DNA methylation in the onset and progression of various cancer types is now being elucidated as more large-scale data become available. The Cancer Genome Atlas (TCGA) provides a wealth of information for the analysis of various molecular aspects of cancer genetics. Gene expression data and DNA methylation data from TCGA have been used for a variety of studies. A traditional understanding of the effects of DNA methylation on gene expression has linked methylation of CpG sites in the gene promoter region with the decrease in gene expression. Recent studies have begun to expand this traditional role of DNA methylation. Results: Here we present a pan-cancer analysis of correlation patterns between CpG methylation and gene expression. Using matching patient data from TCGA, 33 cancer-specific correlations were calculated for each CpG site and the expression level of its corresponding gene. These correlations were used to identify patterns on a per-site basis as well as patterns of methylation across the gene body. Using these identified patterns, we found genes that contain conflicting methylation signals beyond the commonly accepted association between the promoter region methylation and silencing of gene expression. Beyond gene body methylation in whole, we examined individual CpG sites and show that, even in the same gene body, some sites can have a contradictory effect on gene expression in cancers. Conclusions: We observed that within promoter regions there was a substantial amount of positive correlation between methylation and gene expression, which contradicts the commonly accepted association. We observed that the correlation between CpG methylation and gene expression does not exhibit in a tissue-specific manner, suggesting that the effects of methylation on gene expression are largely tissue independent. The analysis of correlation associated with the location of the CpG site in the gene body has led to the identification of several different methylation patterns that affect gene expression, and several examples of methylation activating gene expression were observed. Distinctly opposing or conflicting effects were seen in close proximity on the gene body, where negative and positive correlations were seen at the neighboring CpG sites.

scholarly journals A region-based method for causal mediation analysis of DNA methylation data

2020 ◽  
Author(s):  
Qi Yan ◽  
Erick Forno ◽  
Juan C. Celedón ◽  
Wei Chen
Keyword(s):  
Dna Methylation ◽  
Indirect Effect ◽  
Mediation Analysis ◽  
Error Rates ◽  
Atopic Asthma ◽  
Type I ◽  
Power Performance ◽  
Cpg Sites ◽  
Cpg Site ◽  
Causal Mediation

ABSTRACTExposure to environmental factors can affect DNA methylation at a CpG site or a genomic region, which can then affect an outcome of interest. In other words, environmental effects on an outcome could be mediated by DNA methylation. To date, single CpG site-based mediation analysis has been employed extensively. More recently, however, there has been considerable interest on studying differentially methylated regions (DMRs), both because DMRs are more likely to have functional effects than single CpG sites and because testing DMRs reduces multiple testing. In this report, we propose a novel causal mediation approach under the counterfactual framework to test the significance of total, direct and indirect effects of predictors on response variable with a methylated region (MR) as the mediator (denoted as MR-Mediation). Functional linear transformation is used to reduce the possible high dimension of the CpG sites in a predefined methylated region and to account for their location information. In our simulation studies, MR-Mediation retained the desired Type I error rates for total, direct and indirect effect tests, for both continuous and binary outcomes. Furthermore, MR-Mediation had better power performance than testing single CpG sites as the mediator in most considered scenarios, especially for indirect effect (i.e., mediated effect) test, which could be more interesting than the other two effect tests. We further illustrate our proposed method by analyzing the methylation mediated effect of exposure to gun violence on total IgE or atopic asthma among participants in the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study.

scholarly journals Paternal DNA Methylation May Be Associated With Gestational Age at Birth

2020 ◽  
Vol 13 ◽  
pp. 251686572093070
Author(s):  
Rui Luo ◽  
Nandini Mukherjee ◽  
Su Chen ◽  
Yu Jiang ◽  
S Hasan Arshad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Membrane ◽  
Gestational Age ◽  
Correlation Coefficients ◽  
Functional Enrichment ◽  
Cpg Sites ◽  
Membrane Adhesion ◽  
Gestational Age At Birth ◽  
Age At Birth

Background: How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites. Methods: Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC. Results: Analysis of DNAm of fathers collected around their partner’s pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin ( PCDH) gene clusters were associated with gene expression of PCDH in F2 cord blood. Conclusions: Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.

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