Tissue-specific dysregulation of DNA methylation in aging
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE17332 | GEO | 2010/05/01
SECONDARY ACCESSION(S): PRJNA119017
REPOSITORIES: GEO
Similar Datasets
Project description:The normal aging process is a complex phenomenon associated with physiological alterations in the function of cells and organs over time. Although an attractive candidate for mediating transcriptional dysregulation, the contribution of epigenetic dysregulation to these progressive changes in cellular function remains unclear. In this study, we employed the genome-wide HELP assay to define patterns of cytosine methylation throughout the rat genome, and the LUMA assay to measure global levels of DNA methylation in the same samples. We studied both liver and visceral adipose tissue, and demonstrated significant differences in DNA methylation with age at >5% of sites analyzed. Furthermore, we showed that epigenetic dysregulation with age is a highly tissue-dependent phenomenon. The most distinctive loci were located at intergenic sequences and conserved non-coding elements, and not at promoters nor at CG-dinucleotide dense loci. Finally, we demonstrated that changes in methylation occur consistently near genes that are involved in metabolism and metabolic regulation, implicating their potential role in the pathogenesis of age-related diseases. We conclude that different patterns of epigenetic dysregulation occur in each tissue over time and may cause some of the physiological changes associated with normal aging. Direct comparison of DNA methylation in 18 samples belonging to four groups: young liver (n=6), young adipose tissue (n=4), old liver (n=5), old adipose tissue (n=3), isolated from F344*BN rats (young at ~3 months, old at ~18 months). Each microarray consists of a two-color comparison of a methylation-sensitive representation of the genome (HpaII) with an internal methylation-insensitive control/reference (MspI).
2010-05-01 | E-GEOD-17332 | biostudies-arrayexpress
Project description:There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4+ T-cells and CD14+ monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ-layer compared with blood, demonstrates that the aDMR signature is a multi-tissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture. We measured the methylation state of 27,578 CpG sites (Illumina HumanMethylation27 array) in whole blood samples from 93 heathy human females aged between 49 and 74, to discover sites which change methylation state with age.
2010-06-24 | E-GEOD-20236 | biostudies-arrayexpress
Project description:Epigenetic changes have been used to estimate chronological age across the lifespan, and some studies suggest that epigenetic "aging" clocks may already operate in developing tissue. To better understand the relationship between developmental stage and epigenetic age, we utilized the highly regular sequence of development found in the mammalian neural retina and a well-established epigenetic aging clock based on DNA methylation. Our results demonstrate that the epigenetic age of fetal retina is highly correlated with chronological age. We further establish that epigenetic aging progresses normally in vitro, suggesting that epigenetic aging is a property of individual tissues. This correlation is also retained in stem cell-derived retinal organoids, but is accelerated in individuals with Down's syndrome, a progeroid-like condition. Overall, our results suggest that epigenetic aging begins as early as a few weeks post-conception, in fetal tissues, and the mechanisms underlying the phenomenon of epigenetic aging might be studied in developing organs.
2021-01-21 | GSE124252 | GEO
Project description:Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed epigenetic drift, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N=108) using array-based profiling of 450,000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovers an age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome. This data set contains data from transcription profiling by array of human epidermis samples. The results of methylation profiling are provided in the ArrayExpress experiment E-MTAB-4385.
2016-03-24 | E-MTAB-4382 | biostudies-arrayexpress
Project description:Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed epigenetic drift, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N=108) using array-based profiling of 450,000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovers an age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome. This data set contains data from methylation profiling by array of human epidermis samples. The results of transcription profiling by array are provided in the ArrayExpress experiment E-MTAB-4382.
2016-03-24 | E-MTAB-4385 | biostudies-arrayexpress
Project description:There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4+ T-cells and CD14+ monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ-layer compared with blood, demonstrates that the aDMR signature is a multi-tissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture. We measured the methylation state of 27,578 CpG sites (Illumina HumanMethylation27 array) in sorted human blood cells to validate aging-associated DMRs.
2010-06-24 | E-GEOD-20242 | biostudies-arrayexpress
Project description:Early postnatal overnutrition causes persistent dysregulation of endocrine pancreas function. We used genome-scale DNA methylation profiling in the suckling-period small litter (SL) mouse model to test whether this occurs via persistent epigenetic changes in pancreatic islets. Although SL islets showed DNA methylation changes directly after weaning and in adulthood, few of these were present at both ages, contrary to our hypothesis. Most interestingly, we discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging. Focusing on a subset of genes relevant to β cell function, we showed that these methylation differences are strongly correlated with expression. Together, our results provide the novel insight that DNA methylation changes that occur as islets age indicate an overall epigenetic drift toward the exocrine pancreas epigenome. These concerted shifts in the islet methylome could contribute to the age-associated decline in endocrine pancreas function. Pancreatic islets were isolated from P21/P180 SL or C mice. To ensure purity of islets, 3 rounds of manual picking were performed in each samples. Whole pancreas samples, ~98% of which is exocrine pancreas, were used as exocrine pancreas. There are 5 mice per group.
2014-12-03 | E-GEOD-63811 | biostudies-arrayexpress
Project description:Tissue-specific dysregulation of DNA methylation in aging
| PRJNA119017 | ENA
Project description:Early postnatal overnutrition causes persistent dysregulation of endocrine pancreas function. We used genome-scale DNA methylation profiling in the suckling-period small litter (SL) mouse model to test whether this occurs via persistent epigenetic changes in pancreatic islets. Although SL islets showed DNA methylation changes directly after weaning and in adulthood, few of these were present at both ages, contrary to our hypothesis. Most interestingly, we discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging. Focusing on a subset of genes relevant to β cell function, we showed that these methylation differences are strongly correlated with expression. Together, our results provide the novel insight that DNA methylation changes that occur as islets age indicate an overall epigenetic drift toward the exocrine pancreas epigenome. These concerted shifts in the islet methylome could contribute to the age-associated decline in endocrine pancreas function.
2014-12-03 | GSE63811 | GEO
Project description:Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variation in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation, and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P < 0.0001), and were significant predictors of tissue origin (P < 0.0001). In solid tissues (n=119) we found striking, highly significant CpG island dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P < 0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age and exposure related differences in tissue-specific methylation, and significant age associated methylation patterns which are CpG island context dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer, and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference. The causes and extent of tissue-specific interindividual variation in human epigenomes are underappreciated and hence, poorly characterized. We surveyed over 200 carefully annotated human tissue samples from ten anatomic sites at 1413 CpGs for methylation alterations to appraise the nature of phenotypically, and hence potentially clinically important epigenomic alterations. Within tissue types, across individuals, we found variation in methylation that was significantly related to aging and environmental exposures such as tobacco smoking. Individual variation in age and exposure-related methylation may significantly contribute to increased susceptibility to several diseases. As the NIH-funded HapMap project is critically contributing to annotating the human reference genome defining normal genetic variability, our work raises key issues to consider in the construction of reference epigenomes. It is well recognized that understanding genetic variation is essential to understanding disease. Our work, and the known interplay of epigenetics and genetics, makes it equally clear that a more complete characterization of epigenetic variation and its sources must be accomplished to reach the goal of a complete understanding of disease. Additional research is absolutely necessary to define the mechanisms controlling epigenomic variation. We have begun to lay the foundations for essential normal tissue controls for comparison to diseased tissue, which will allow the identification of the most crucial disease-related alterations and provide more robust targets for novel treatments.
2009-12-12 | GSE19434 | GEO