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Aging and epigenetics: longitudinal changes in gene-specific DNA methylation.

ABSTRACT: DNA methylation has been associated with age-related disease. Intra-individual changes in gene-specific DNA methylation over time in a community-based cohort has not been well described. We estimated the change in DNA methylation due to aging for nine genes in an elderly, community-dwelling cohort of men. Seven hundred and eighty four men from the Veterans Administration Normative Aging Study who were living in metropolitan Boston from 1999-2009 donated a blood sample for DNA methylation analysis at clinical examinations repeated at approximately 3-5 year intervals. We used mixed effects regression models. Aging was significantly associated with decreased methylation of GCR, iNOS and TLR2 and with increased methylation of IFN?, F3, CRAT and OGG. Obstructive pulmonary disease at baseline modified the effect of aging on methylation of IFN? (interaction p = 0.04). For participants who had obstructive pulmonary disease at their baseline visit, the rate of change of methylation of IFN? was -0.05% 5-methyl-cytosine (5-mC) per year (95% CI: -0.22, 0.13), but was 0.14% 5-mC per year (95% CI: 0.05, 0.24) for those without this condition. Models with random slopes indicated significant heterogeneity in the effect of aging on methylation of GCR, iNOS and OGG. These findings suggest that DNA methylation may reflect differential biological aging.

SUBMITTER: Madrigano J

PROVIDER: S-EPMC3329504 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Aging and epigenetics: longitudinal changes in gene-specific DNA methylation.

Madrigano Jaime J Baccarelli Andrea A Mittleman Murray A MA Sparrow David D Vokonas Pantel S PS Tarantini Letizia L Schwartz Joel J

Epigenetics 20120101 1

DNA methylation has been associated with age-related disease. Intra-individual changes in gene-specific DNA methylation over time in a community-based cohort has not been well described. We estimated the change in DNA methylation due to aging for nine genes in an elderly, community-dwelling cohort of men. Seven hundred and eighty four men from the Veterans Administration Normative Aging Study who were living in metropolitan Boston from 1999-2009 donated a blood sample for DNA methylation analysi ...[more]

PMID: 22207354

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Project description:Recent research suggests that epigenetics, especially DNA methylation, plays a mechanistic role in aging. Epigenetic clocks, which measure changes in a few hundred specific CpG sites, can accurately predict chronological age in a variety of species, including humans. These clocks are currently the best biomarkers for predicting mortality in humans. Additionally, several studies have characterized the effects of aging across the methylome in a wide variety of tissues from humans and mice. A small fraction (~2%) of the CpG sites show age-related changes, either hypermethylation or hypomethylation with aging. Evaluation of non-CpG site methylation has only been examined in a few studies, with about ~0.5% of these sites showing a change with age. Therefore, while only a small fraction of cytosines in the genome show changes in DNA methylation with age, this represents 2 to 3 million cytosines in the genome. Importantly, the only study to compare the effect of aging on DNA methylation in male and female mice and humans found that >95% of the age-related changes in DNA methylation in the hippocampus were sexually divergent, i.e., the methylation did not differ between males and females at young age but age-related changes occurred in one sex but not the other. The age-related changes in DNA methylation tend to be enriched and under-represented in specific genomic contexts, with some commonalities between tissues and species that require further investigation. The strongest evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, dwarfism, and rapamycin treatment) in mice. These anti-aging interventions deaccelerate the epigenetic clocks and reverse/prevent 20 to 40% of the age-related changes in DNA methylation. It will be important in the future to demonstrate that at least some of the age-related changes in DNA methylation directly lead to alterations in the transcriptome of cells/tissues that could potentially contribute to aging.

Project description:BackgroundEarly life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies.MethodsTo this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects.ResultsWe found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements.ConclusionsThese data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life.

Project description:Incomplete recovery of blood-brain barrier (BBB) function contributes to stroke outcomes. How the BBB recovers after stroke remains largely unknown. Emerging evidence suggests that epigenetic factors play a significant role in regulating post-stroke BBB recovery. This study aimed to evaluate the epigenetic and transcriptional profile of cerebral microvessels after thromboembolic (TE) stroke to define potential causes of limited BBB recovery. RNA-sequencing and reduced representation bisulfite sequencing (RRBS) analyses were performed using microvessels isolated from young (6 months) and old (18 months) mice seven days poststroke compared to age-matched sham controls. DNA methylation profiling of poststroke brain microvessels revealed 11,287 differentially methylated regions (DMR) in old and 9818 DMR in young mice, corresponding to annotated genes. These DMR were enriched in genes encoding cell structural proteins (e.g., cell junction, and cell polarity, actin cytoskeleton, extracellular matrix), transporters and channels (e.g., potassium transmembrane transporter, organic anion and inorganic cation transporters, calcium ion transport), and proteins involved in endothelial cell processes (e.g., angiogenesis/vasculogenesis, cell signaling and transcription regulation). Integrated analysis of methylation and RNA sequencing identified changes in cell junctions (occludin), actin remodeling (ezrin) as well as signaling pathways like Rho GTPase (RhoA and Cdc42ep4). Aging as a hub of aberrant methylation affected BBB recovery processes by profound alterations (hypermethylation and repression) in structural protein expression (e.g., claudin-5) as well as activation of a set of genes involved in endothelial to mesenchymal transformation (e.g., Sox9, Snai1), repression of angiogenesis and epigenetic regulation. These findings revealed that DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration and prevalently with processes enhancing BBB injury.

Dataset Information

Aging and epigenetics: longitudinal changes in gene-specific DNA methylation.

Publications

Aging and epigenetics: longitudinal changes in gene-specific DNA methylation.

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