Project description:Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (M-NM-^TYOM-bM-^@M-^I>M-bM-^@M-^I5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression. Peripheral blood mononuclear cells were isolated from 10 volunteers (5 young 5 old), treated with the synthetic PPARalpha agonists WY14,643 or control for 13 hrs, and subjected to genome-wide DNA methylation and gene expression analysis. This entry contains the DNA methylation data.

Project description:Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (M-NM-^TYOM-bM-^@M-^I>M-bM-^@M-^I5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression. Peripheral blood mononuclear cells were isolated from 10 volunteers (5 young 5 old), treated with the synthetic PPARalpha agonists WY14,643 or control for 13 hrs, and subjected to genome-wide DNA methylation and gene expression analysis. This entry contains the gene expression data.

Project description:Interplanetary human spaceflight represents a formidable medical challenge, but also provides a unique platform for investigating human adaptation to extreme environmental changes. Understanding the long-term effects of isolation has relevance in a range of scenarios and it is well recognized that a better understanding of the relationship between environmental exposure and the epigenome can lead to more effective preventive measures. Here we conduct a longitudinal epigenetic, mood state and biochemical profiling of 6 crew members in an experiment simulating a 520-day mission to Mars. Illumina HumanMethylation450 BeadChip was used to obtain DNA methylation profiles. Firstly, we found that long-term isolation can induce global DNA methylation remodeling, and this change seems to be an active adaptation (rather than a random process or a by-product of the isolation). This study is the first to demonstrate the dynamic relationship between global epigenetic remodeling and isolation-induced mood state and biochemical changes. Secondly, by considering the location of methylation sites within the genome and using gene-pathway annotation, we were able to identify pathways that were significantly enriched in methylation events and consider their association with specific function and the timeline of the mission. Thirdly, via our definition of epi-entropy, a measure of entropy adapted to methylation events, we observed that the methylation remodeling produced a marked reduction in epi-entropy. Results suggest that DNA methylation change is an indicator of change rather than its by-product, i.e., there is a psychology-epigenome-metabolism model of long-term depression; DNA methylation programs the environment signal into the epigenome, which is subsequently transformed into the biochemical output and health outcome. Thus, longitudinal epigenetic profiling could code the effect of isolation and act as early indicators of latent health outcome. A longitudinal epigenetic, mood state and biochemical profiling of 6 crew members in an experiment simulating a 520-day mission to Mars. 36 samples of blood cell DNA methylation profiling were obtained by Illumina HumanMethylation450 BeadChip, across 6 sampling points during the 520 days mission for all of the 6 crew members.

Project description:Preeclampsia is one of the leading causes of maternal death worldwide. While the root cause is still unknown, the underlying biology of the disorder is becoming more clear. We recently published a study showing large, significant differences in DNA methylation in 3rd trimester placental samples associated with early-onset preeclampsia (EOPET) compared to controls. In this study, to identify DNA methylation differences associated with preeclampsia that occur early in pregnancy and to further delineate common EOPET-associated differences, we utilized a genetic defect, trisomy 16 (T16), that is predisposing to preeclampsia. We ran T16 placental samples from the 1st trimester (n=5) and 3rd trimester (n=10) against gestational age matched controls on the Illumina Infinium HumanMethylation450 BeadChip. Third trimester samples were from pregnancies with T16 confined to the placenta (confined placental mosaicism 16;CPM16), and consisted of samples that were and were not associated with EOPET (n=5 each). We identified a large number of DNA methylation differences in CPM16 samples compared to controls using stringent criteria (n=2254;False Discovery Rate <0.01, ->0.15). Several of these differences (11%) overlapped differences observed in chromosomally normal EOPET using similarly stringent criteria (FDR<0.01;->0.125). Isolating EOPET-associated probes produced a similar - distribution amongst CPM16 samples, although samples associated with EOPET showed a tendency towards larger DNA methylation differences. We also identified 262 DNA methylation differences between 1st trimester T16 and 1st trimester controls. Of these, 77 overlapped differences seen in 3rd trimester CPM16. Investigating these 77 T16/CPM16 specific DNA methylation differences, we identified three probes near two genes (ARGHEF37 and JUNB) that were also present as EOPET-associated methylation differences. In summary, we identified significant overlapping DNA methylation profiles of placentas with T16 and chromosomally normal placentas associated with EOPET. Specific DNA methylation marks within these profiles may be of future clinical utility in early identification of pregnancies susceptible to EOPET. Bisulfite converted DNA from 5 1st trimester trisomy 16 placentas, 5 chromosomally normal 1st trimester placentas, 10 third trimester placentas from confined placental mosaicism placentas and 10 chromosomally normal 3rd trimester placentas

Project description:Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still able to adapt adequately to changes in energy balance. Therefore studying the changes that occur on appetite regulators in the hypothalamus might reveal targets for treatment of cancer-induced eating disorders. By applying transcriptomics, many appetite regulating systems in the hypothalamus could be taken into account, providing an overview of changes that occur in the hypothalamus during tumour growth. We show that hypothalamic expression of orexigenic neuropeptides NPY and AgRP was higher, whereas expression of anorexigenic genes CCK and POMC were lower in TB compared to controls. In addition, serotonin and dopamine signalling pathways were found to be significantly altered in TB mice. Serotonin levels in brain showed to be lower in TB mice compared to control mice, while dopamine levels did not change. Moreover, serotonin levels inversely correlated with food intake. Transcriptomic analysis of the hypothalamus of cachectic TB mice with an increased food intake showed changes in NPY, AgRP and serotonin signalling. Serotonin levels in the brain showed to correlate with changes in food intake. Targeting these systems seems a promising strategy to avoid the development of cancer-induced eating disorders. C26-colon adenocarcinoma cells were subcutaneously inoculated in CDF1 mice. After 20 days, hypothalami were dissected and subjected to gene expression profiling. The total dataset consists of 2 parts; dataset 1, a pilot stuy in which mice were injected with increasing number of tumour cells and pooled samples were arrayed; and dataset 2, the main study in which mice were injected with 1 million tumour cells and samples were individually arrayed.

Dataset Information

Aging-induced differential methylation in human PBMCs occurs with but often without change in expression of the associated gene

Publications

Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs.

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