scholarly journals Age and mortality associated DNA methylation patterns on the X-chromosome in male and female samples

2019 ◽  
Author(s):  
Shuxia Li ◽  
Jesper B. Lund ◽  
Jan Baumbach ◽  
Kaare Christensen ◽  
Jonas Mengel-From ◽  
...  
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Association Studies ◽  
Male And Female ◽  
Chromosome 20 ◽  
Age Related ◽  
Large Numbers ◽  
Genome Wide ◽  
Lothian Birth Cohort ◽  
Methylation Patterns

AbstractBackgroundMultiple epigenetic association studies on human aging have been performed reporting large numbers of sites differentially methylated across ages on the autosomal chromosomes. The X-chromosome has been studied little, due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation in females. Based on large collections of genome-wide DNA methylation data on two Danish cohorts of identical twins (mean ages, 66 and 79 years) and the Lothian Birth Cohort 1921 (mean age 79 years), we conducted a chromosome-wide association analysis on male and female samples separately with equal sample sizes to discover age-dependent X-linked DNA methylation patterns using chromosome 20 with about same number of CpGs analysed as an autosomal reference, and compare the age-related changes in DNA methylation between the two sexes. In addition, age-related methylation sites were assessed for their associations with mortality.ResultsWe identified more age-related DNA methylation sites (FDR<0.05) in females than in males. Among them, predominantly more sites were hypermethylated in the older as compared with the younger cohorts, a pattern similar to that observed on chromosome 20. Among the age-related sites, 13 CpGs in males and 24 CpGs in females were found significant (FDR<0.05) in all cohorts. Survival analysis showed that there are more age-methylated CpGs that contribute to reduce mortality than those that increase mortality in male but not in female samples.ConclusionThe X-chromosome displays significant age-and sex-dependent methylation patterns which might be differentially associated with mortality in the two sexes.

scholarly journals Epigenetic modifications and their role in the development and disease progression of type 2 diabetes

2021 ◽  
Vol 8 (2) ◽  
pp. 948
Author(s):  
Abhijeet Roy
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Epigenetic Regulation ◽  
Association Studies ◽  
Normal Subjects ◽  
Genome Wide Association Studies ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Methylation Patterns

Type 2 Diabetes is one of the major public health issues and a complex metabolic disorder strongly associated with genetic predisposition influenced by environmental factors and epigenetic regulation. This review paper illustrated the role of epigenetics in the pathogenesis, progression, and detection of Type 2 Diabetes. A review study was performed for the articles published in English from 2000-2019 using Pub Med, and Google Scholar databases. Main underlining mechanisms of Type 2 Diabetes were identified; insulin resistance in the peripheral tissue, and disintegrate insulin secretion. Genome Wide Association Studies suggested that epigenetic regulation such as DNA methylation, Histone modification, Non-coding RNA, microRNA is strongly related with the development of Type 2 Diabetes. Altered DNA methylation patterns in pancreatic islets, skeletal muscle, adipose tissue, from diabetic subjects compare to normal subjects was also found. Other risk factors like; obesity, age, gender, impaired glucose tolerance, periconception and intrauterine environment may also have been linked with the possibilities of epigenetic changes. Epigenetics plays a crucial role by modifying the gene expression and establish a relationship between the environment and genetic factors. Understanding the epigenetic mechanisms contributing to the development of Type 2 Diabetes is still limited.

scholarly journals Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

2017 ◽  
Author(s):  
Yunzhang Wang ◽  
Robert Karlsson ◽  
Erik Lampa ◽  
Qian Zhang ◽  
Åsa K. Hedman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Monozygotic Twins ◽  
Cross Sectional ◽  
Age Related ◽  
Genome Wide ◽  
Illumina Humanmethylation450 ◽  
Binding Factor ◽  
Old Swedish ◽  
Methylation Patterns ◽  
Over Time

AbstractAge-related changes in DNA methylation have been observed in many cross-sectional studies, but longitudinal evidence is still very limited. Here, we aimed to characterize longitudinal age-related methylation patterns (Illumina HumanMethylation450 array) using 1011 blood samples collected from 385 old Swedish twins (mean age of 69 at baseline) up to five times over 20 years. We identified 1316 age-associated methylation sites (p<1.3×10−7) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in PIVUS (p<3.9×10−5) and 594 were replicated in LBC (p<5.1×10−5). Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other unannotated transcription factor binding sites. We further investigated genetic influences on methylation (methylation quantitative trait loci) and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased over time, where monozygotic twins had smaller intra-pair differences than dizygotic twins. We show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. Moreover, the changes are under genetic influence, although this effect is independent of age. In addition, inter-individual methylation variations increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

scholarly journals Genome-wide DNA methylation dynamics during epigenetic reprogramming in the porcine germline

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Isabel Gómez-Redondo ◽  
Benjamín Planells ◽  
Sebastián Cánovas ◽  
Elena Ivanova ◽  
Gavin Kelsey ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Germ Cells ◽  
Time Course ◽  
Blastocyst Stage ◽  
Epigenetic Reprogramming ◽  
Male And Female ◽  
Large Numbers ◽  
Genome Wide ◽  
Bisulphite Sequencing ◽  
General Dynamics

Abstract Background Prior work in mice has shown that some retrotransposed elements remain substantially methylated during DNA methylation reprogramming of germ cells. In the pig, however, information about this process is scarce. The present study was designed to examine the methylation profiles of porcine germ cells during the time course of epigenetic reprogramming. Results Sows were artificially inseminated, and their fetuses were collected 28, 32, 36, 39, and 42 days later. At each time point, genital ridges were dissected from the mesonephros and germ cells were isolated through magnetic-activated cell sorting using an anti-SSEA-1 antibody, and recovered germ cells were subjected to whole-genome bisulphite sequencing. Methylation levels were quantified using SeqMonk software by performing an unbiased analysis, and persistently methylated regions (PMRs) in each sex were determined to extract those regions showing 50% or more methylation. Most genomic elements underwent a dramatic loss of methylation from day 28 to day 36, when the lowest levels were shown. By day 42, there was evidence for the initiation of genomic re-methylation. We identified a total of 1456 and 1122 PMRs in male and female germ cells, respectively, and large numbers of transposable elements (SINEs, LINEs, and LTRs) were found to be located within these PMRs. Twenty-one percent of the introns located in these PMRs were found to be the first introns of a gene, suggesting their regulatory role in the expression of these genes. Interestingly, most of the identified PMRs were demethylated at the blastocyst stage. Conclusions Our findings indicate that methylation reprogramming in pig germ cells follows the general dynamics shown in mice and human, unveiling genomic elements that behave differently between male and female germ cells.

scholarly journals Sexually divergent DNA methylation programs with hippocampal aging

2017 ◽  
Author(s):  
Dustin R. Masser ◽  
Niran Hadad ◽  
Hunter Porter ◽  
Colleen A. Mangold ◽  
Archana Unnikrishnan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sex Differences ◽  
Biological Aging ◽  
Age Related ◽  
Genome Wide ◽  
Aging Response ◽  
Genomic Location ◽  
Methylation Patterns ◽  
Genomic Methylation

SummaryDNA methylation is a central regulator of genome function and altered methylation patterns are indicative of biological aging and mortality. Age-related cellular, biochemical, and molecular changes in the hippocampus lead to cognitive impairments and greater vulnerability to neurodegenerative disease that varies between the sexes. The role of hippocampal epigenomic changes with aging in these processes is unknown as no genome-wide analyses of age-related methylation changes have considered the factor of sex in a controlled animal model. High-depth, genome-wide bisulfite sequencing of young (3 month) and old (24 month) male and female mouse hippocampus revealed that while total genomic methylation amounts did not change with aging, specific sites in CG and non-CG (CH) contexts demonstrated age-related increases or decreases in methylation that were predominantly sexually divergent. Differential methylation with age for both CG and CH sites was enriched in intergenic, and intronic regions and under-represented in promoters, CG islands and specific enhancer regions in both sexes suggesting that certain genomic elements are especially labile with aging, even if the exact genomic loci altered are predominantly sex-specific. Life-long sex differences in autosomal methylation at CG and CH sites were also observed. The lack of genome-wide hypomethylation, sexually divergent aging response, and autosomal sex differences at CG sites were confirmed in human data. These data reveal sex as a previously unappreciated central factor of hippocampal epigenomic changes with aging. In total, these data demonstrate an intricate regulation of DNA methylation with aging by sex, cytosine context, genomic location, and methylation level.

scholarly journals Genome-wide Methylation Patterns Under Caloric Restriction inDaphnia magna

2018 ◽  
Author(s):  
Jack Hearn ◽  
Marianne Pearson ◽  
Mark Blaxter ◽  
Philip Wilson ◽  
Tom J. Little
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Caloric Intake ◽  
Functional Link ◽  
Age Related ◽  
Genome Wide ◽  
Bisulphite Sequencing ◽  
Effects Of Aging ◽  
Methylation Patterns ◽  
The Impact

AbstractThe degradation of epigenetic control with age is associated with progressive diseases of ageing, including cancers, immunodeficiency and diabetes. Reduced caloric intake slows the effects of aging and age-related diseases, a process likely to be mediated by the impact of caloric restriction on epigenetic factors such as DNA methylation. We used whole genome bisulphite sequencing to study how DNA methylation patterns change with diet in a small invertebrate, the crustaceanDaphnia magna.Daphniashow the classic response of longer life under CR, and they reproduce clonally, which permits the study of epigenetic changes in the absence of genetic variation. Global CpG methylation was 0.7-0.9%, and there was no difference in overall methylation levels between normal and calorie restricted replicates. However, 453 regions were differentially methylated (DMRs) between the normally fed and calorie restricted (CR) replicates. Of these 61% were hypomethylated in the CR group, and 39% were hypermethylated in the CR group. Gene Ontogeny (GO) term enrichment of hyper and hypo-methylated genes showed significant over- and under-representation in three molecular function terms and four biological process GO terms. Notable among these were kinase and phosphorylation activity, which have a well-known functional link to cancers.

scholarly journals Divergent DNA methylation signatures of X chromosome regulation in marsupials and eutherians

2020 ◽  
Author(s):  
Devika Singh ◽  
Dan Sun ◽  
Andrew G. King ◽  
David E. Alquezar-Planas ◽  
Rebecca N. Johnson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Specific Expression ◽  
X Chromosomes ◽  
Phascolarctos Cinereus ◽  
Male And Female ◽  
Inactive X Chromosome ◽  
Genome Wide ◽  
Promoter Dna Methylation ◽  
Promoter Dna

AbstractX chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is well characterized in eutherian mammals. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here we examine genome-wide signatures of DNA methylation from methylation maps across fives tissues from a male and female koala (Phascolarctos cinereus) and present the first whole genome, multi-tissue marsupial “methylome atlas.” Using these novel data, we elucidate divergent versus common features of marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in marsupials primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx, the primary lncRNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-(and presumably inactive X chromosome-) specific expression. Finally, we utilize the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5 %) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

Abstract MP31: DNA Methylation Patterns are Associated with Genetic Variation and Systemic Inflammation

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Stella Aslibekyan ◽  
Alexis C Frazier-Wood ◽  
Devin M Absher ◽  
Jin Sha ◽  
Degui Zhi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Systemic Inflammation ◽  
Quantitative Trait ◽  
Inflammatory Marker ◽  
Lipid Lowering ◽  
Chromosome 11 ◽  
Chromosome 20 ◽  
Genome Wide ◽  
A Genome ◽  
Methylation Patterns

Introduction: Chronic systemic inflammation is a complex trait characterized by moderate to high heritability and important implications for cardiovascular health. Previously identified genetic polymorphisms explain only a modest fraction of variability in circulating inflammatory marker concentrations. Hypothesis: We hypothesized that variation in DNA methylation patterns contributes to the missing heritability of inflammatory traits, and that such associations may in turn be influenced by environmental factors (smoking, alcohol, and obesity) as well as common genetic variants. Methods: Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 593), we assayed the methylation status of approximately 450,000 sites across the genome and measured serum concentrations of high-sensitivity C-reactive protein (hsCRP), soluble interleukin-2 receptor alpha (sIL2Ra), interleukin-6 (IL6), tumor necrosis factor alpha (TNFa), and monocyte chemoattractant protein 1 (MCP1). To investigate and validate the associations between DNA methylation patterns and systemic inflammation, we split the GOLDN data set into discovery (n= 451) and replication (n= 142) data sets. During the discovery stage, we modeled continuous methylation scores at each site on inflammatory markers, adjusted for age, sex, study site, and T-cell purity as fixed effects and family structure as a random effect. Results: After correcting for multiple comparisons, the strongest signal was obtained from an intergenic CpG island on chromosome 20 and levels of hsCRP (P=5×10-10) and sILR2a (P=6×10-6). Our findings are consistent with previous linkage studies that have identified a quantitative trait locus for inflammation in an adjacent region of chromosome 20. Moreover, the association with sIL2Ra but not hsCRP was observed in replication analyses (P=0.008). Models adjusting for current smoking status, alcohol consumption, or body mass index did not appreciably change the estimates of association. Finally, we performed a genome-wide analysis to identify quantitative trait loci for methylation of the CpG site on chromosome 20. We found a genome-wide significant (P=3×10×-8) association with rs11223480 on chromosome 11 in OPCML, which encodes a tumor suppressor, and suggestive (P<4×10-6) associations with a cluster of 9 variants located on chromosome 20 in MACROD2, a gene previously reported to be associated with systemic inflammation. Conclusions: We have conducted the first integrated study of epigenetic variation, genotype, and circulating inflammatory marker concentrations. In conclusion, our findings suggest that differential methylation of an intergenic region on chromosome 20, likely in conjunction with the underlying genotype, is associated with systemic inflammation and merits further evaluation as a cardiovascular risk factor.

scholarly journals Age-related DNA methylation changes are sex-specific: a comprehensive assessment

2020 ◽  
Author(s):  
Igor Yusipov ◽  
Maria Giulia Bacalini ◽  
Alena Kalyakulina ◽  
Mikhail Krivonosov ◽  
Chiara Pirazzini ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sex Differences ◽  
Meta Analysis ◽  
Large Fraction ◽  
Age Related ◽  
Genome Wide ◽  
Epigenetic Age ◽  
Age Dependent ◽  
Males And Females ◽  
Methylation Patterns

AbstractIn humans, females live longer than males but experience a worse longevity, as genome-wide autosomal DNA methylation differences between males and females have been reported. So far, few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes shows age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes, and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and in entropy, we showed that the number of probes showing age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.

scholarly journals Trends in DNA methylation with age replicate across diverse human populations

2016 ◽  
Author(s):  
Shyamalika Gopalan ◽  
Oana Carja ◽  
Maud Fagny ◽  
Etienne Patin ◽  
Justin W. Myrick ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Meta Analysis ◽  
Chronological Age ◽  
Human Populations ◽  
Strongly Correlated ◽  
Hunter Gatherers ◽  
Cpg Sites ◽  
Age Related ◽  
Genome Wide ◽  
Methylation Patterns

AbstractAging is associated with widespread changes in genome-wide patterns of DNA methylation. Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with chronological age have been previously identified. However, the majority of these studies have focused primarily on cosmopolitan populations living in the developed world; it is not known if age-related patterns of DNA methylation at these loci are similar across a broad range of human genetic and ecological diversity. We investigated genome-wide methylation patterns using saliva and whole blood derived DNA from two traditionally hunting and gathering African populations: the Baka of the western Central African rainforest and the ≠Khomani San of the South African Kalahari Desert. We identify hundreds of CpG sites whose methylation levels are significantly associated with age, thousands that are significant in a meta-analysis, and replicate trends previously reported in populations of non-African descent. We confirm that an age-associated site in the gene ELOVL2 shows a remarkably congruent relationship with aging in humans, despite extensive genetic and environmental variation across populations. We also demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect methylation trends at some known age-associated CpG sites. Our study explores the relationship between CpG methylation and chronological age in populations of African hunter-gatherers, who rely on different diets across diverse ecologies. While many age-related CpG sites replicate across populations, we show that considering common genetic variation at meQTLs further improves our ability to detect previously identified age associations.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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