scholarly journals The Impact of DNA Methylation Dynamics on the Mutation Rate During Human Germline Development

2020 ◽  
Vol 10 (9) ◽  
pp. 3337-3346
Author(s):  
Yijia Zhou ◽  
Funan He ◽  
Weilin Pu ◽  
Xun Gu ◽  
Jiucun Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mutation Rate ◽  
Germline Mutation ◽  
Developmental Stages ◽  
Rare Variants ◽  
Epigenetic Modification ◽  
Genome Project ◽  
Germline Development ◽  
Cpg Sites ◽  
The Impact

Abstract DNA methylation is a dynamic epigenetic modification found in most eukaryotic genomes. It is known to lead to a high CpG to TpG mutation rate. However, the relationship between the methylation dynamics in germline development and the germline mutation rate remains unexplored. In this study, we used whole genome bisulfite sequencing (WGBS) data of cells at 13 stages of human germline development and rare variants from the 1000 Genome Project as proxies for germline mutations to investigate the correlation between dynamic methylation levels and germline mutation rates at different scales. At the single-site level, we found a significant correlation between methylation and the germline point mutation rate at CpG sites during germline developmental stages. Then we explored the mutability of methylation dynamics in all stages. Our results also showed a broad correlation between the regional methylation level and the rate of C > T mutation at CpG sites in all genomic regions, especially in intronic regions; a similar link was also seen at all chromosomal levels. Our findings indicate that the dynamic DNA methylome during human germline development has a broader mutational impact than is commonly assumed.

Abstract 428: DNA Methylation of ASC is Associated with Decreased ASC and IL-1β Expression in Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Brittany Butts ◽  
Javed Butler
Keyword(s):  
Heart Failure ◽  
Dna Methylation ◽  
Inflammatory Cytokines ◽  
Epigenetic Modification ◽  
Cpg Islands ◽  
Inflammasome Activation ◽  
Cpg Sites ◽  
Exon 1 ◽  
Vital Component ◽  
Intron Region

Introduction: Heart failure (HF) is associated with formation and activation of inflammasome, a complex of intracellular interaction proteins that trigger maturation of inflammatory cytokines to initiate inflammatory response. ASC, a vital component of the inflammasome, is controlled through epigenetic modification via methylation of CpG islands surrounding exon 1. Methods: To assess the relationships between DNA methylation of ASC, ASC expression, and inflammatory cytokines IL-1β and IL-18 in HF, stored samples from 155 chronic HF patients (age 56.9±12.0 yr, 64% male, 47% black, and ejection fraction 29.9±14.9) were analyzed. DNA extracted from PMBCs were analyzed by pyrosequencing for percent methylation of seven CpG sites in the intron region preceding exon 1 of the ASC gene. ASC mRNA was quantified via real-time PCR and analyzed as the ratio ASC:GAPDH. Serum ASC, IL-1β, and IL-18 were measured by ELISA. Results: Higher ASC methylation was associated with lower ASC mRNA (r=0-.328, p<0.001) and protein (r=-.464, p<0.001) expression. Lower ASC mRNA expression was associated with lower ASC protein expression (r=0.494, p<0.001). Decreased IL-1β expression was associated with higher ASC methylation (r=-.424, p=0.005) and lower ASC mRNA (r=.619, p<0.001) and ASC protein (r=.433, p<0.001). IL-18 expression was not significantly associated with ASC methylation or expression. Conclusions: Increased ASC methylation was associated with lower IL-1β, likely via decreased ASC gene expression. As ASC is required for inflammasome activation of IL-1β, this study implicates the inflammasome pathway as a driver of inflammation in HF, proving a potential target for novel interventions.

scholarly journals The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2004 ◽  
Author(s):  
Terisha Ghazi ◽  
Thilona Arumugam ◽  
Ashmika Foolchand ◽  
Anil A. Chuturgoon
Keyword(s):  
Dna Methylation ◽  
Bioactive Compounds ◽  
Epigenetic Modification ◽  
Bioactive Molecules ◽  
Methyl Donors ◽  
Food Borne ◽  
One Carbon Metabolism ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns ◽  
The Impact

Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.

scholarly journals DNA Methylation Reprogramming during Sex Determination and Transition in Zebrafish

2020 ◽  
Author(s):  
Xinxin Wang ◽  
Xin Ma ◽  
Gaobo Wei ◽  
Weirui Ma ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sex Determination ◽  
Sexual Development ◽  
Epigenetic Modification ◽  
Sex Differentiation ◽  
Primordial Germ Cells ◽  
Regulation Of Gene Expression ◽  
Adult Zebrafish ◽  
Germline Development ◽  
Male Sex

AbstractIt is a mystery about sex determination and sexual plasticity in species without sex chromosomes. DNA methylation is a prevalent epigenetic modification in vertebrates, which has been shown to involve in the regulation of gene expression and embryo development. However, it remains unclear about how DNA methylation regulates sexual development. To elucidate it, we used zebrafish to investigate DNA methylation reprogramming during juvenile germ cell development and adult female-to-male sex transition. We revealed that primordial germ cells (PGCs) undergo significant DNA methylation reprogramming during germline development and set to an oocyte/ovary-like pattern at 9 days post fertilization (9 dpf). When blocking DNMTs activity in juveniles after 9 dpf, the zebrafish preferably develops into females. We also show that Tet3 involves in PGC development. Notably, we find that DNA methylome reprogramming during adult zebrafish sex transition is similar to the reprogramming during the sex differentiation from 9 dpf PGCs to sperm. Furthermore, inhibiting DNMTs activity can prevent the female-to-male sex transition, suggesting that methylation reprogramming is required for zebrafish sex transition. In summary, DNA methylation plays important roles in zebrafish germline development and sexual plasticity.

scholarly journals Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Ines Verlinden ◽  
Fabian Güiza ◽  
Inge Derese ◽  
Pieter J. Wouters ◽  
Koen Joosten ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Critical Illness ◽  
Parenteral Nutrition ◽  
Time Course ◽  
De Novo ◽  
Healthy Children ◽  
Cpg Sites ◽  
A Genome ◽  
Early Parenteral Nutrition ◽  
The Impact

Abstract Background A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantified DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients differed from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identified different patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites affected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already differentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.

scholarly journals DNA methylation patterns of β-globin cluster in β-thalassemia patients

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiuqin Bao ◽  
Yangjin Zuo ◽  
Diyu Chen ◽  
Cunyou Zhao
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Methylation Level ◽  
Epigenetic Modification ◽  
Fetal Hemoglobin ◽  
Cpg Sites ◽  
Hbf Level ◽  
Globin Promoter ◽  
Methylation Patterns ◽  
Normal Controls

Abstract Background Reactivation of fetal hemoglobin (HbF, α2γ2) holds a therapeutic target for β-thalassemia and sickle cell disease. Although many HbF regulators have been identified, the methylation patterns in β-globin cluster driving the fetal-to-adult hemoglobin switch remains to be determined. Results Here, we evaluated DNA methylation patterns of the β-globin cluster from peripheral bloods of 105 β0/β0 thalassemia patients and 44 normal controls. We also recruited 15 bone marrows and 4 cord blood samples for further evaluation. We identified that the CpG sites in the locus control region (LCR) DNase I hypersensitive site 4 and 3 (HS4-3) regions, and γ- and β-globin promoters displayed hypomethylation in β0/β0-thalassemia patients, especially for the patients with high HbF level, as compared with normal controls. Furthermore, hypomethylations in most of CpG sites of the HS4-3 core regions were also observed in bone marrows (BM) of β0/β0-patients compared with normal controls; and methylation level of γ-globin promoter -50 and + 17 CpG sites showed lower methylation level in patients with high HbF level compared with those with low HbF level and a negative correlation with HbF level among β0-thalassemia patients. Finally, γ-globin promoter + 17 and + 50 CpG sites also displayed significant hypomethylation in cord blood (CB) tissues compared with BM tissues from normal controls. Conclusions Our findings revealed methylation patterns in β-globin cluster associated with β0 thalassemia disease and γ-globin expression, contributed to understand the epigenetic modification in β0 thalassemia patients and provided candidate targets for the therapies of β-hemoglobinopathies.

DNA methylation in the vertebrate germline: balancing memory and erasure

2019 ◽  
Vol 63 (6) ◽  
pp. 649-661 ◽  
Author(s):  
Oscar Ortega-Recalde ◽  
Timothy Alexander Hore
Keyword(s):  
Dna Methylation ◽  
Cytosine Methylation ◽  
Epigenetic Modification ◽  
Epigenetic Inheritance ◽  
Direct Consequence ◽  
Early Embryo ◽  
Germline Development ◽  
Evolutionary Mechanisms ◽  
Information Module ◽  
Methylation Patterns

Abstract Cytosine methylation is a DNA modification that is critical for vertebrate development and provides a plastic yet stable information module in addition to the DNA code. DNA methylation memory establishment, maintenance and erasure is carefully balanced by molecular machinery highly conserved among vertebrates. In mammals, extensive erasure of epigenetic marks, including 5-methylcytosine (5mC), is a hallmark of early embryo and germline development. Conversely, global cytosine methylation patterns are preserved in at least some non-mammalian vertebrates over comparable developmental windows. The evolutionary mechanisms which drove this divergence are unknown, nevertheless a direct consequence of retaining epigenetic memory in the form of 5mC is the enhanced potential for transgenerational epigenetic inheritance (TEI). Given that DNA methylation dynamics remains underexplored in most vertebrate lineages, the extent of information transferred to offspring by epigenetic modification might be underestimated.

scholarly journals Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Jedidiah Carlson ◽  
◽  
Adam E. Locke ◽  
Matthew Flickinger ◽  
Matthew Zawistowski ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
Rare Variants ◽  
Rate Heterogeneity

scholarly journals 0027 Adolescent Sleep Timing And Dietary Patterns In Relation To Dna Methylation Of Core Clock Genes

SLEEP ◽  
2019 ◽  
Vol 42 (Supplement_1) ◽  
pp. A11-A11
Author(s):  
Erica C Jansen ◽  
Dana Dolinoy ◽  
Ronald D Chervin ◽  
Karen E Peterson ◽  
Louise M O'Brien ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dietary Patterns ◽  
Dietary Habits ◽  
Clock Genes ◽  
Epigenetic Modification ◽  
Shift Workers ◽  
Wake Time ◽  
Cpg Sites ◽  
Sleep Timing ◽  
Increased Risk

Abstract Introduction Mistimed sleep/wake and eating patterns put adult shift workers at increased risk for chronic disease, and epigenetic modification of core clock genes has been proposed as a mechanism. Although not as extreme as shift workers, adolescents often have delayed sleep timing. Our aim was to assess whether sleep midpoints in adolescents are associated with DNA methylation of circadian genes. A secondary aim was to examine associations between dietary patterns and circadian gene methylation. Methods The study population included 142 Mexican youth (average age 14.0 (SD=2.0) years, 49% male) enrolled in a cohort study. Average sleep midpoint (between bed time and wake time) over 7 days was estimated with actigraphy. Diet was assessed with a semi-quantitative food frequency questionnaire, and three dietary patterns were derived from principal components analysis (a vegetable-based pattern, a meat and starch-based pattern, and a breakfast pattern). DNA methylation was quantified in blood leukocytes with the Infinium MethylatinEPIC BeadChip. We selected 166 loci (CpG sites) within CpG islands of core ‘clock’ genes known to regulate circadian rhythms (CLOCK, BMAL, PER1, PER2, PER3, CRY1, CRYI2, RORA, RORB, REV-VERBA, REV-VERBB). Linear regression was used to analyze associations between sleep midpoint or dietary patterns and logit-transformed percent methylation at the 166 CpG sites. All models were adjusted for sex and age. Results The average midpoint was 3:41 AM (SD=1 hr 15 min); average bed time was 11:29 PM (SD=68 min) and average wake time was 7:53 AM (SD=97 min). Sleep midpoint was positively associated with DNA methylation of CpG sites from the genes REV-VERBA and RORB at the Bonferroni-corrected significance level of p&lt;0.005. The breakfast dietary pattern (rich in eggs, milk, and bread) was inversely associated with DNA methylation at RORA (P=0.003). Conclusion Sleep timing and dietary habits are associated with DNA methylation of core clock genes in adolescents. Epigenetic modification of clock genes could in part underlie relationships between sleep, diet, and metabolic health among adolescents. Support (If Any) Dr. Jansen is supported by the NIH/NHLBI grant 5T32HL110952-05.

scholarly journals Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ and sex specific

2020 ◽  
Vol 318 (3) ◽  
pp. L549-L561
Author(s):  
Zhijun Zeng ◽  
Karolin F. Meyer ◽  
Khosbayar Lkhagvadorj ◽  
Wierd Kooistra ◽  
Marjan Reinders-Luinge ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Large Scale ◽  
Developmental Stages ◽  
Association Studies ◽  
Inverse Correlation ◽  
Cpg Sites ◽  
Increased Risk ◽  
Organ Specific ◽  
Health And Disease

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.

scholarly journals Obesity and menopause modify the epigenomic profile of breast cancer

2017 ◽  
pp. 351-363 ◽  
Author(s):  
Ana B Crujeiras ◽  
Angel Diaz-Lagares ◽  
Olafur A Stefansson ◽  
Manuel Macias-Gonzalez ◽  
Juan Sandoval ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
High Risk ◽  
Risk Group ◽  
Menopausal Status ◽  
Breast Tumors ◽  
Methylation Pattern ◽  
High Risk Group ◽  
Cpg Sites ◽  
The Impact

Obesity is a high risk factor for breast cancer. This relationship could be marked by a specific methylome. The current work was aimed to explore the impact of obesity and menopausal status on variation in breast cancer methylomes. Data from Infinium 450K array-based methylomes of 64 breast tumors were coupled with information on BMI and menopausal status. Additionally, DNA methylation results were validated in 18 non-tumor and 81 tumor breast samples. Breast tumors arising in either pre- or postmenopausal women stratified by BMI or menopausal status alone were not associated with a specific DNA methylation pattern. Intriguingly, the DNA methylation pattern identified in association with the high-risk group (postmenopausal women with high BMI (>25) and premenopausal women with normal or low BMI < 25) exclusively characterized by hypermethylation of 1287 CpG sites as compared with the low-risk group. These CpG sites included the promoter region of fourteen protein-coding genes of which CpG methylation over the ZNF577 promoter region represents the top scoring associated event. In an independent cohort, the ZNF577 promoter methylation remained statistically significant in association with the high-risk group. Additionally, the impact of ZNF577 promoter methylation on mRNA expression levels was demonstrated in breast cancer cell lines after treatment with a demethylating agent (5-azacytidine). In conclusion, the epigenome of breast tumors is affected by a complex interaction between BMI and menopausal status. The ZNF577 methylation quantification is clearly relevant for the development of novel biomarkers of precision therapy in breast cancer.

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