New Targeted Approaches for Epigenetic Age Predictions
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151641 | GEO | 2020/06/03
REPOSITORIES: GEO
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Project description:Age-associated DNA methylation reflects aspect of biological aging - therefore epigenetic clocks for mice can help to elucidate the impact of treatments or genetic background on the aging process in this model organism. Initially, age-predictors for mice were trained for genome-wide DNA methylation profiles and we have recently described a targeted assay based on pyrosequencing of DNA methylation at only three CG dinucleotides (CpGs). Here, we have re-evaluated pyrosequencing approaches in comparison to droplet digital PCR (ddPCR) and barcoded bisulfite amplicon sequencing (BBA-seq). At individual CpGs the correlation of DNA methylation with chronological age was slightly higher for pyrosequencing and ddPCR as compared to BBA-seq. On the other hand, BBA-seq revealed that neighboring CpGs tend to be stochastically modified at murine age-associated regions. Furthermore, the binary sequel of methylated and non-methylated CpGs in individual reads can be used for single-read predictions, which may reflect heterogeneity in epigenetic aging. In comparison to C57BL/6 mice the epigenetic age-predictions using BBA-seq were also accelerated in the shorter-lived DBA/2 mice, and in C57BL/6 mice with a lifespan quantitative trait locus of DBA/2 mice. Taken together, we describe further optimized and alternative targeted methods to determine epigenetic clocks in mice.
2020-08-14 | GSE156193 | GEO
Project description:Osteoporosis is an age-related metabolic bone disease. Hence, osteoporotic patients might suffer from molecular features of accelerated aging, which is generally reflected by specific age-associated DNA methylation (DNAm) changes. In this study, we analyzed genome wide DNAm profiles of peripheral blood from patients with manifest primary osteoporosis and non-osteoporotic controls. Statistical analysis did not reveal any individual CG dinucleotides (CpG sites) with significant aberrant DNAm in osteoporosis. Subsequently, we analyzed if age-associated DNAm patterns are increased in OP. Using three independent age-predictors we did not find any evidence for accelerated epigenetic age in blood of osteoporotic patients. Taken together, osteoporosis is not reflected by characteristic DNAm patterns of peripheral blood that might be used as biomarker for the disease. The prevalence of osteoporosis is age-associated – but it is not associated with premature epigenetic aging in peripheral blood.
2018-03-13 | GSE99624 | GEO
Project description:Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes These changes might be directly regulated or caused by gradual deregulation of the epigenetic state, which is often referred to as “epigenetic drift” We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types During reprogramming into induced pluripotent stem cells (iPSCs) particularly the culture-associated hypomethylation is reversed simultaneously with age-associated and pluripotency-associated DNAm changes Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpolulations of MSCs at later passages Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no preferential interaction with other genomic regions that also harbor culture-associated DNAm changes Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF Taken together, our results indicate that DNAm changes during culture-expansion resembles epigenetic drift
2021-05-26 | GSE116375 | GEO
Project description:Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes. These changes might be directly regulated or caused by gradual deregulation of the epigenetic state, which is often referred to as “epigenetic drift”. We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types. During reprogramming into induced pluripotent stem cells (iPSCs) particularly the culture-associated hypomethylation is reversed simultaneously with age-associated and pluripotency-associated DNAm changes. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpolulations of MSCs at later passages. Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no preferential interaction with other genomic regions that also harbor culture-associated DNAm changes. Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF. Taken together, our results indicate that DNAm changes during culture-expansion resembles epigenetic drift.
2021-05-26 | GSE165603 | GEO
Project description:Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes at specific sites in the genome. These changes might be due to an directly regulated epigenetic process, or to gradual deregulation of the epigenetic state, which is often referred to as “epigenetic drift”. We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types. During reprogramming into induced pluripotent stem cells (iPSCs) the long-term culture-associated hypomethylation is reversed simultaneously with pluripotency-associated DNAm changes. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to dominant subclones at later passages. Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no preferential interaction with other genomic regions that also harbor culture-associated DNAm changes. Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF. Taken together, the DNAm changes during culture-expansion of cells cannot be attributed to cellular subsets, whereas they seem to resemble epigenetic drift in relation to chromatin conformation.
2021-05-26 | GSE144195 | GEO
Project description:Age predictors based on DNA methylation levels at a small set of CpG sites, DNAm clocks, have been developed for humans and extended to several other species. Three currently available versions of mouse DNAm clocks were either created for individual tissues or tuned towards young ages. Here, we constructed a robust multi-tissue age predictor based on 435 CpG sites, which covers the entire mouse lifespan and remains unbiased with respect to any particular age group. It can successfully detect the effects of several lifespan-modulating interventions on biological age as well as the rejuvenation effect related to the transition from fibroblasts to iPSCs. We have carried out comparative analyses of available mouse DNAm clocks, which revealed their broad applicability, but also certain limitations to the use of tissue-specific and multi-tissue age predictors. Together, these tools should help address diverse questions in aging research.
2018-11-20 | GSE121141 | GEO
Project description:Standardization of mesenchymal stromal cells (MSCs) remains a major obstacle in regenerative medicine. Starting material and culture expansion affect cell preparations and render comparison between studies difficult. In contrast, induced pluripotent stem cells (iPSCs) assimilate towards a ground-state and may therefore give rise to more standardized cell preparations. We reprogrammed bone marrow MSCs into iPSCs which were subsequently re-differentiated towards MSCs. These iPS-MSCs revealed similar morphology, immunophenotype, in vitro differentiation potential, and gene expression profiles as primary MSCs. DNA methylation (DNAm) profiles of iPSCs maintained some donor-specific characteristics, whereas tissue-specific, senescence-associated, and age-related DNAm patterns were erased during reprogramming. iPS-MSCs reacquired senescence-associated DNAm during culture expansion but they remained rejuvenated with regard to age-related DNAm. Overall, iPS-MSCs and MSCs are similar in function but differ in their epigenetic makeup. 8 samples were hybridized to the GeneChip Human Gene 1.0 ST Array (Affymetrix)
2014-09-24 | E-GEOD-54766 | biostudies-arrayexpress
Project description:Standardization of mesenchymal stromal cells (MSCs) remains a major obstacle in regenerative medicine. Starting material and culture expansion affect cell preparations and render comparison between studies difficult. In contrast, induced pluripotent stem cells (iPSCs) assimilate towards a ground-state and may therefore give rise to more standardized cell preparations. We reprogrammed bone marrow MSCs into iPSCs which were subsequently re-differentiated towards MSCs. These iPS-MSCs revealed similar morphology, immunophenotype, in vitro differentiation potential, and gene expression profiles as primary MSCs. DNA methylation (DNAm) profiles of iPSCs maintained some donor-specific characteristics, whereas tissue-specific, senescence-associated, and age-related DNAm patterns were erased during reprogramming. iPS-MSCs reacquired senescence-associated DNAm during culture expansion but they remained rejuvenated with regard to age-related DNAm. Overall, iPS-MSCs and MSCs are similar in function but differ in their epigenetic makeup. 12 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip
2014-09-24 | E-GEOD-54767 | biostudies-arrayexpress
Project description:DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis and early development, monozygotic twins show indistinguishable childhood methylation, suggesting DNAm is highly coordinated during the pediatric period. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from 398 boys, aged 3 to 17 years, and find significant age-associated changes in DNAm at 2,078 loci. We report a deficit of such loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. These pediatric age-associated loci overlap significantly with those previously identified in adults (p < 0.001) but most of the pediatric loci are unique, suggesting many are childhood-specific. Meta-analysis (n = 1080) with two adult studies reveals that the methylation changes in 29.5% of the age-associated pediatric loci follow a linear pattern from childhood into adulthood; however, we also find a three-fold higher rate of change in children compared with adults and that a higher proportion of lifelong changes are more accurately modeled as a function of logarithmic age. We therefore conclude that DNAm changes occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies are matched closely for age. Age associated DNA methylation was evaluated at each CpG locus using a fixed-effects linear regression model adjusting for BeadChip as a covariate to account for batch effects. Analysis of variance (ANOVA) was conducted for each CpG locus to assess the age affect at each CpG locus which was subsequently corrected for multiple hypotheses using a Benjamini-Hochberg FDR. SUPPLEMENTARY FILES: * Matrix_AllSampleDetection.txt: Detection P-values for each sample and each loci * Matrix_AllSampleSignal.txt: Signal for Probe A and Probe B for each sample and each loci * Matrix_Non-Normalized_AllSampleBeta.txt: Beta values calculated using GenomeStudio v2010.3 Methylation Module 1.8.5 as Signal of Probe B / (Signal of Probe A + Signal of Probe B + 100) * Matrix_Normalized_AllSampleBetaPrime.txt: Beta Prime values used for analysis calculated from the Probe B and Probe A signals as Beta Prime = Signal of Probe B / (Signal of Probe A + Signal of Probe A)
2012-02-01 | E-GEOD-27097 | biostudies-arrayexpress
Project description:Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting. The survival model containing only the methylomic predictors was superior in terms of predictive accuracy compared with the models containing the conventional predictors body mass index and mini-mental state examination. At the 2.55-year follow-up, we identified 19 mortality-associated (false-discovery rate <0.5) CpG sites that mapped to genes functionally clustering around the nuclear factor kappa B (NF-κB) complex. Interestingly, none of the mortality-associated CpG sites overlapped with the established aging-associated DNAm sites. Our results are in line with previous findings on the role of NF-κB in controlling animal life spans and demonstrate the key role of this complex in human longevity.
2017-02-09 | GSE68194 | GEO