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 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 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 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 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 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 DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jack Hearn ◽  
Fiona Plenderleith ◽  
Tom J. Little
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Daphnia Magna ◽  
Single Gene ◽  
Methylation Status ◽  
Strain Differences ◽  
Life History Trait ◽  
Food Level ◽  
Epigenetic Clock ◽  
Age Related

Abstract Background Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna. Results Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age. Conclusions Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.

scholarly journals Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Todd R. Robeck ◽  
Zhe Fei ◽  
Ake T. Lu ◽  
Amin Haghani ◽  
Eve Jourdain ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Age Estimation ◽  
Species Conservation ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Highly Correlated ◽  
Methylation Patterns ◽  
Cg Dinucleotides ◽  
Free Ranging ◽  
Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

scholarly journals Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wardah Mahmood ◽  
Lars Erichsen ◽  
Pauline Ott ◽  
Wolfgang A. Schulz ◽  
Johannes C. Fischer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Free Dna ◽  
The Past ◽  
Free Dna ◽  
Genome Wide ◽  
Cancerous Cell ◽  
Pure Cell ◽  
Epigenetic Biomarker ◽  
Methylation Patterns ◽  
Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

scholarly journals DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3587
Author(s):  
Benjamin Lebecque ◽  
Céline Bourgne ◽  
Véronique Vidal ◽  
Marc G. Berger
Keyword(s):  
Dna Methylation ◽  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Single Gene ◽  
Clonal Heterogeneity ◽  
Sequencing Technologies ◽  
Genome Wide ◽  
The Impact

Chronic Myeloid Leukemia (CML) is a model to investigate the impact of tumor intra-clonal heterogeneity in personalized medicine. Indeed, tyrosine kinase inhibitors (TKIs) target the BCR-ABL fusion protein, which is considered the major CML driver. TKI use has highlighted the existence of intra-clonal heterogeneity, as indicated by the persistence of a minority subclone for several years despite the presence of the target fusion protein in all cells. Epigenetic modifications could partly explain this heterogeneity. This review summarizes the results of DNA methylation studies in CML. Next-generation sequencing technologies allowed for moving from single-gene to genome-wide analyses showing that methylation abnormalities are much more widespread in CML cells. These data showed that global hypomethylation is associated with hypermethylation of specific sites already at diagnosis in the early phase of CML. The BCR-ABL-independence of some methylation profile alterations and the recent demonstration of the initial intra-clonal DNA methylation heterogeneity suggests that some DNA methylation alterations may be biomarkers of TKI sensitivity/resistance and of disease progression risk. These results also open perspectives for understanding the epigenetic/genetic background of CML predisposition and for developing new therapeutic strategies.

scholarly journals Disease-associated DNA methylation signatures in esophageal biopsies of children diagnosed with Eosinophilic Esophagitis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Caterina Strisciuglio ◽  
Felicity Payne ◽  
Komal Nayak ◽  
Marialuisa Andreozzi ◽  
Alessandra Vitale ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Eosinophilic Esophagitis ◽  
Field Potential ◽  
Line Treatment ◽  
Food Impaction ◽  
First Line ◽  
Genome Wide ◽  
Epigenetic Signatures ◽  
The Impact ◽  
First Line Treatment

AbstractEosinophilic esophagitis (EoE) is a leading cause of dysphagia and food impaction in children and adults. The diagnosis relies on histological examination of esophageal mucosal biopsies and requires the presence of > 15 eosinophils per high-powered field. Potential pitfalls include the impact of biopsy sectioning as well as regional variations of eosinophil density. We performed genome-wide DNA methylation analyses on 30 esophageal biopsies obtained from children diagnosed with EoE (n = 7) and matched controls (n = 13) at the time of diagnosis as well as following first-line treatment. Analyses revealed striking disease-associated differences in mucosal DNA methylation profiles in children diagnosed with EoE, highlighting the potential for these epigenetic signatures to be developed into clinically applicable biomarkers.

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