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Summary: DNA methylation is an essential epigenetic modification for gene regulation in plant growth and development. However, the precise mechanisms of DNA methylation remain poorly understood, especially in woody plants.We employed whole‐genome bisulfite sequencing (WGBS), assays for transposase‐accessible chromatin using sequencing (ATAC‐seq), and RNA‐Seq to investigate epigenetic regulatory relationships in Populus tomentosa treated with DNA methylation inhibitor 5‐azacitidine. Expression‐quantitative trait methylation analysis (eQTM), epigenome‐wide association study (EWAS), and joint linkage‐linkage disequilibrium mapping were used to explore the epigenetic regulatory genes, and using CRISPR/Cas9 to identify the role of candidate genes.Plant developmental abnormalities occurred when DNA methylation levels were substantially reduced. DNA methylation regulated 112 expressed genes via chromatin accessibility, of which 61 genes were significantly influenced by DNA methylation variation at the population level. One DNA methylation‐regulated gene, PtoGntK, was located in a major quantitative trait locus (QTL) for poplar growth. Overexpression and CRISPR/Cas9 of PtoGntK revealed it affected poplar height and stem diameter. The PtoRAP2.12 was found to bind to the demethylated accessible region in the PtoGntK promoter, thereby promoting growth in poplar.This study identified key genes with epigenetic regulation for plant growth and provides insights into epigenetic regulation mechanisms in woody plants. [ABSTRACT FROM AUTHOR]

As a potential link between genetic predisposition, environmental exposures, and food allergy outcomes, epigenetics has been a molecular variable of interest in ongoing efforts to understand food allergy mechanisms and outcomes. Here we review population‐based investigations of epigenetic loci associated with food allergy, focusing on established clinical food allergy. We first provide an overview of epigenetic mechanisms that have been studied in cohorts with food allergy, predominantly DNA methylation but also microRNA. We then discuss investigations that have implemented epigenome‐wide approaches aimed at genome‐wide profiling and discovery. Such epigenome‐wide studies have collectively identified differentially methylated and differentially regulated loci associated with T cell development, antigen presentation, reaction severity, and causal mediation in food allergy. We then discuss candidate‐gene investigations that have honed in on Th1, Th2, T regulatory, and innate genes of a priori interest in food allergy. These studies have highlighted methylation changes in specific candidate genes as associated with T regulatory cell activity as well as differential methylation of Type 1 and Type 2 cytokine genes associated with various food allergies. Intriguingly, epigenetic loci associated with food allergy have also been explored as potential biomarkers for the clinical management of food allergy. We conclude by highlighting several priority directions for advancing population‐based epigenomic and epigenetic understandings of food allergy. [ABSTRACT FROM AUTHOR]

Background: Little is currently known about epigenetic alterations associated with body composition in obesity. Thus, we aimed to explore epigenetic relationships between genome‐wide DNA methylation levels and three common traits of body composition as measured by body fat percentage (BF%), fat mass (FM) and lean body mass (LBM) among Chinese monozygotic twins. Methods: Generalized estimated equation model was used to regress the methylation level of CpG sites on body composition. Inference about Causation Through Examination Of Familial Confounding was used to explore the evidence of a causal relationship. Gene expression analysis was further performed to validate the results of differentially methylated genes. Results: We identified 32, 22 and 28 differentially methylated CpG sites (p < 10−5) as well as 20, 17 and eight differentially methylated regions (slk‐corrected p < 0.05) significantly associated with BF%, FM and LBM which were annotated to 65 genes, showing partially overlapping. Causal inference demonstrated bidirectional causality between DNA methylation and body composition (p < 0.05). Gene expression analysis revealed significant correlations between expression levels of five differentially methylated genes and body composition (p < 0.05). Conclusions: These DNA methylation signatures will contribute to increased knowledge about the epigenetic basis of body composition and provide new strategies for early prevention and treatment of obesity and its related diseases. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Recent studies revealed the association of abnormal methylomic changes with Alzheimer's disease (AD) but there is a lack of systematic study of the impact of methylomic alterations over the molecular networks underlying AD. METHODS: We profiled genome‐wide methylomic variations in the parahippocampal gyrus from 201 post mortem control, mild cognitive impaired, and AD brains. RESULTS: We identified 270 distinct differentially methylated regions (DMRs) associated with AD. We quantified the impact of these DMRs on each gene and each protein as well as gene and protein co‐expression networks. DNA methylation had a profound impact on both AD‐associated gene/protein modules and their key regulators. We further integrated the matched multi‐omics data to show the impact of DNA methylation on chromatin accessibility, which further modulates gene and protein expression. DISCUSSION: The quantified impact of DNA methylation on gene and protein networks underlying AD identified potential upstream epigenetic regulators of AD. Highlights: A cohort of DNA methylation data in the parahippocampal gyrus was developed from 201 post mortem control, mild cognitive impaired, and Alzheimer's disease (AD) brains.Two hundred seventy distinct differentially methylated regions (DMRs) were found to be associated with AD compared to normal control.A metric was developed to quantify methylation impact on each gene and each protein.DNA methylation was found to have a profound impact on not only the AD‐associated gene modules but also key regulators of the gene and protein networks.Key findings were validated in an independent multi‐omics cohort in AD.The impact of DNA methylation on chromatin accessibility was also investigated by integrating the matched methylomic, epigenomic, transcriptomic, and proteomic data. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to systematically review the evidence across studies that assessed DNA methylome variations in association with food allergy (FA). Design: A systematic review of the literature and meta‐analysis were carried out within several databases. However, the risk of bias in the included articles was not evaluated. Data sources PubMed, Cochrane Database of Systematic Reviews, and Web of Science were used to search up to July 2022. Eligibility criteria: We included targeted and epigenome‐wide association studies (EWASs) that assessed DNA methylome alterations in association with FA in adult or paediatric populations. Results: Among 366 publications, only 16 were retained, which were mainly focused on FA in children. Seven candidate gene‐targeted studies found associations in Th1/Th2 imbalance (IL4, IL5, IL10, INFG, IL2 and IL12B genes), regulatory T cell function (FOXP3 gene), Toll‐like receptors pathway (TLR2, CD14 genes) and digestive barrier integrity (FLG gene). Nine EWAS assessed the association with peanut allergy (n = 3), cow's milk allergy (n = 2) or various food allergens (n = 4). They highlighted 11 differentially methylated loci in at least two studies (RPS6KA2, CAMTA1, CTBP2, RYR2, TRAPPC9, DOCK1, GALNTL4, HDAC4, UMODL1, ZAK and TNS3 genes). Among them, CAMTA1 and RPS6KA2, and CTBP2 are involved in regulatory T cell function and Th2 cell differentiation, respectively. Gene‐functional analysis revealed two enriched gene clusters involved in immune responses and protein phosphorylation. ChIP‐X Enrichment Analysis 3 showed eight significant transcription factors (RXRA, ZBTB7A, ESR1, TCF3, MYOD1, CTCF, GATA3 and CBX2). Ingenuity Pathway Analysis identified canonical pathways involved, among other, in B cell development, pathogen‐induced cytokine storm signalling pathway and dendritic cell maturation. Conclusion: This review highlights the involvement of epigenomic alterations of loci in Th1/Th2 and regulatory T cell differentiation in both candidate gene studies and EWAS. These alterations provide a better insight into the mechanistic aspects in FA pathogenesis and may guide the development of epigenome‐based biomarkers for FA. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome‐wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions. [ABSTRACT FROM AUTHOR]

Cattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. To facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several DNA methylation‐based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. One such clock was germane to only oocytes, while a dual‐tissue clock was highly predictive of age in both oocytes and blood. Dual species clocks that apply to both humans and cattle were also developed and evaluated. These epigenetic clocks can be used to accurately estimate the biological age of oocytes. Both epigenetic clock studies and epigenome‐wide association studies revealed that blood and oocytes differ substantially with respect to aging and the underlying epigenetic signatures that potentially influence the aging process. The rate of epigenetic aging was found to be slower in oocytes compared to blood; however, oocytes appeared to begin at an older epigenetic age. The epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes. [ABSTRACT FROM AUTHOR]

Background: DNA methylation may play a role in the progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. We examined the association between alcohol consumption and DNA methylation patterns using 3 approaches: a conventional epigenome‐wide association study (EWAS); a co‐twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption. Methods: Participants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1,004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome‐wide DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. Results: In the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co‐twin comparisons replicated 4 CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker vs. light drinker/abstainer or moderate drinker vs. abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co‐twins. Conclusions: Our analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood. [ABSTRACT FROM AUTHOR]

DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10-7 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1414 cross-sectional associations. Our study indicates that alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with alcohol consumption changes in adulthood. [ABSTRACT FROM AUTHOR]

Aims: Natriuretic peptides are useful for diagnosis and prognostication of heart failure of any cause. Now, research aims to discover novel biomarkers that will more specifically define the heart failure phenotype. DNA methylation plays a critical role in the development of cardiovascular disease with the potential to predict fundamental pathogenic processes. There is a lack of data relating DNA methylation in heart failure that specifically focuses on patients with severe multi‐vessel coronary artery disease. To begin to address this, we conducted a pilot study uniquely exploring the utility of powerful whole‐genome methyl‐binding domain‐capture sequencing in a cohort of cardiac surgery patients, matched for the severity of their coronary artery disease, aiming to identify candidate peripheral blood DNA methylation markers of ischaemic cardiomyopathy and heart failure. Methods and results: We recruited a cohort of 20 male patients presenting for coronary artery bypass graft surgery with phenotypic extremes of heart failure but who otherwise share a similar coronary ischaemic burden, age, sex, and ethnicity. Methylation profiling in patient blood samples was performed using methyl‐binding domain‐capture sequencing. Differentially methylated regions were validated using targeted bisulfite sequencing. Gene set enrichment analysis was performed to identify differences in methylation at or near gene promoters in certain known Reactome pathways. We detected 567 188 methylation peaks of which our general linear model identified 68 significantly differentially methylated regions in heart failure with a false discovery rate <0.05. Of these regions, 48 occurred within gene bodies and 25 were located near enhancer elements, some within coding genes and some in non‐coding genes. Gene set enrichment analyses identified 103 significantly enriched gene sets (false discovery rate <0.05) in heart failure. Validation analysis of regions with the strongest differential methylation data was performed for two genes: HDAC9 and the uncharacterized miRNA gene MIR3675. Genes of particular interest as novel candidate markers of the heart failure phenotype with reduced methylation were HDAC9, JARID2, and GREM1 and with increased methylation PDSS2. Conclusions: We demonstrate the utility of methyl‐binding domain‐capture sequencing to evaluate peripheral blood DNA methylation markers in a cohort of cardiac surgical patients with severe multi‐vessel coronary artery disease and phenotypic extremes of heart failure. The differential methylation status of specific coding genes identified are candidates for larger longitudinal studies. We have further demonstrated the value and feasibility of examining DNA methylation during the perioperative period to highlight biological pathways and processes contributing to complex phenotypes. [ABSTRACT FROM AUTHOR]

Background: Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations in DNA methylation. Thus, DNA methylation signatures in peripheral cells may provide biomarkers of the medical impact of alcohol use and the risk for future alcohol consumption. Method: Using a high‐density methylation array, we characterized epigenome‐wide DNA methylation in saliva cells with respect to alcohol consumption in a large cohort of male European American veterans. In this study, DNA methylation of over 870,000 CpG DNA sites was profiled in 1,135 European American men. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test‐Consumption (AUDIT‐C). Linear regression was applied in an epigenome‐wide association study (EWAS), adjusted for confounders. Gene set enrichment analysis was performed in the KEGG database with a correction for gene length. Results: We found that a total of 70 CpG sites reached EWAS‐corrected significance (p < 6E‐08) with small effects on alcohol consumption for individual CpG sites, including 64 new CpG sites and 6 CpG sites that were previously reported as associated with alcohol use disorder, liver function, body mass index, and lipid metabolism. The most significant CpG site was located in SLC7A11 (t = −11.34, p = 2.66E‐28), a gene involved specifically in cysteine and glutamate transportation. The 70 significant CpG sites were located on 44 genes, including genes involved in amino acid transport and metabolism systems. We identified 68 pathways with a false discovery rate < 0.05. Conclusions: We identified novel DNA methylation sites associated with alcohol consumption. Results may shed light on peripheral mechanisms of alcohol consumption on adverse health outcomes among heavy drinkers. [ABSTRACT FROM AUTHOR]

Background: Epigenetics may play a role in wheezing and asthma development. We aimed to examine infant saliva DNA methylation in association with early childhood wheezing. Methods: A case‐control study was nested within the NINFEA birth cohort with 68 cases matched to 68 controls by sex, age (between 6 and 18 months, median: 10.3 months) and season at saliva sampling. Using a bumphunting region–based approach, we examined associations between saliva methylome measured using Illumina Infinium HumanMethylation450k array and wheezing between 6 and 18 months of age. We tested our main findings in independent publicly available data sets of childhood respiratory allergy and atopic asthma, with DNA methylation measured in different tissues and at different ages. Results: We identified one wheezing‐associated differentially methylated region (DMR) spanning ten sequential CpG sites in the promoter‐regulatory region of PM20D1 gene (family‐wise error rate < 0.05). The observed associations were enhanced in children born to atopic mothers. In the publicly available data sets, hypermethylation in the same region of PM20D1 was consistently found at different ages and in all analysed tissues (cord blood, blood, saliva and nasal epithelia) of children with respiratory allergy/atopic asthma compared with controls. Conclusion: This study suggests that PM20D1 hypermethylation is associated with early childhood wheezing. Directionally consistent epigenetic alteration observed in cord blood and other tissues at older ages in children with respiratory allergy and atopic asthma provides suggestive evidence that a long‐term epigenetic modification, likely operating from birth, may be involved in childhood atopic phenotypes. [ABSTRACT FROM AUTHOR]

This study aimed to examine whether the relationship between mothers' DNA methylation profiles and offspring's depression is modulated by negative parenting. The participants were 35 African‐American mother–offspring dyads. Young adult offspring (19 females; age = 17–29.5 years) were assessed on depressive symptoms, and mothers (36–51 years) were assessed on negative parenting. Methyl‐binding domain (MBD) sequencing was used to assay genome‐wide DNA methylation in peripheral T lymphocytes. Controlling for the effect of offspring's DNA methylation, mothers' DNA methylation was positively associated with offspring's depression. Hypermethylation of a subset of the epigenetic markers was associated with increased negative parenting. Negative parenting was positively correlated with offspring's depression as well, suggesting that negative parenting may be a modulator between the mother's epigenome and offspring's depression. This study is one of the first investigations of the modulating role of parenting behavior in associations between the mother's epigenome and offspring's depression. [ABSTRACT FROM AUTHOR]

Recent studies have suggested a role for epigenetic mechanisms in the complex etiology of various neurodegenerative diseases. In this review, we discuss advances that have been made toward understanding the role of epigenetic processes in neurodegenerative disorders, with a particular focus on Alzheimer's disease, where the most extensive studies have been undertaken to date. We provide a brief overview of DNA modifications, followed by a summarization of studies of DNA modifications in Alzheimer's disease and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long-lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy. Methods In a subset of 18-year-old participants from the Isle of Wight (IoW) birth cohort ( n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome-wide DNA methylation was measured, and season-associated CpGs detected using a training-and-testing-based technique. Validation method examined the 8-year-old Prevention and Incidence of Asthma and Mite Allergy ( PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third-generation cohort newborns. Results Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome-wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season-associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season-associated methylation was largely absent in newborns, suggesting it arises post-natally. Conclusions This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved. [ABSTRACT FROM AUTHOR]

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries., (© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Cannabis use is highly prevalent and is associated with adverse and beneficial effects. To better understand the full spectrum of health consequences, biomarkers that accurately classify cannabis use are needed. DNA methylation (DNAm) is an excellent candidate, yet no blood-based epigenome-wide association studies (EWAS) in humans exist. We conducted an EWAS of lifetime cannabis use (ever vs. never) using blood-based DNAm data from a case-cohort study within Sister Study, a prospective cohort of women at risk of developing breast cancer (Discovery N = 1,730 [855 ever users]; Replication N = 853 [392 ever users]). We identified and replicated an association with lifetime cannabis use at cg15973234 (CEMIP): combined p = 3.3 × 10 -8 . We found no overlap between published blood-based cis-meQTLs of cg15973234 and reported lifetime cannabis use-associated single nucleotide polymorphism (SNPs; p < .05), suggesting that the observed DNAm difference was driven by cannabis exposure. We also developed a multi-CpG classifier of lifetime cannabis use using penalized regression of top EWAS CpGs. The resulting 50-CpG classifier produced an area under the curve (AUC) = 0.74 (95% CI [0.72, 0.76], p = 2.00 × 10 -5 ) in the discovery sample and AUC = 0.54 ([0.51, 0.57], p = 2.87 × 10 -2 ) in the replication sample. Our EWAS findings provide evidence that blood-based DNAm is associated with lifetime cannabis use., (© 2020 Wiley Periodicals LLC.)