Novel regional age-associated DNA methylation changes within human common disease-associated loci
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PROVIDER: EGAS00001001910 | EGA |
REPOSITORIES: EGA
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Project description:Context: While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to development of ageing-associated diseases, in human primary muscle stem cells (myoblasts) from community dwelling older individuals we investigated whether differential DNA methylation was associated with IR. Methods: We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 male/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated Cytosine phosphate Guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR (derived from fasting insulin/glucose) and HbA1c. Results: 38 dmCpGs (false discovery rate (FDR)<0.05), and 8 DMRs (Stouffer<0.05) were associated with HOMA2-IR; 6 dmCpGs and 3 DMRs were robust to adjustment for BMI, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2). HOMA2-IR associated dmCpGs were enriched in genes linked with skeletal muscle development and insulin signalling. 49 dmCpGs were associated with HbA1c, with 48 robust to adjustment for BMI. The only dmCpG associated with both HOMA2-IR and HbA1c was cg13451048, located within Exoribonuclease Family Member 3 (ERI3). HOMA2-IR and HbA1c dmCpGs were not associated with accelerated epigenetic ageing. Conclusions: These findings suggest differential DNA methylation in muscle stem cells may contribute to age-related decline in glycaemic control. The identification of dmCpGs, associated genes and pathways may provide novel targets for pharmacological intervention.
2023-11-16 | GSE221540 | GEO
Project description:The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older males (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) – a novel, cell-type specific signature of aging in DNA methylome. Hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells.
2022-02-16 | PXD021821 | Pride
Project description:DNA methylation is critical for development and is strongly associated with gene regulation. Variation in the DNA methylome between closely related species may reveal unique functional adaptation. We have implemented a novel inter-primate DNA methylation genome-wide analysis between human, chimpanzee and rhesus macaque to identify human species-specific Differentially Methylated Regions (human s-DMRs) in orthologous loci. We analysed the peripheral blood cell DNA methylomes of these primates and identified 22,758 hypomethylated and 15,858 hypermethylated human s-DMRs. These s-DMRs are globally enriched within weak promoter, enhancer and transcribed regions via comparison with ChromHMM segmentation. Human s-DMRs, (both hypo- and hypermethylated) are found to be more prevalent in CpG Island shores than within the islands themselves (?2 P = 1.80 x 10-32). Examining human-specific Transcription Factor Binding Site motif change within CpG islands, we show gain and loss, in hypomethylated and hypermethylated s-DMRs, respectively, of CTCF motifs. Epigenetically the most divergent human-specific locus was the immunological Leukotriene B4 receptor (LTB4R, aka BLT1 receptor), due to collocating hypomethylated s-DMRs within the promoter CpG island and shore, as well as inverse increased gene body methylation. This gene is vital in host immune responses and associated with the pathogenesis of a wide range of human inflammatory diseases. This finding was supported by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Functional investigation of the consequences of these epigenetic differences identified this receptor to have increased expression, and have a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness. DNA methylome analysis of pooled Human, Chimpanzee and Macaque
2014-02-01 | E-GEOD-48942 | biostudies-arrayexpress
Project description:Regulation of gene expression by DNA methylation is crucial for defining cellular identities and coordinating organism-wide developmental programs in many organisms. In plants, modulation of DNA methylation in response to environmental conditions represents a potentially robust mechanism to regulate gene expression networks, however, examples of dynamic DNA methylation are largely limited to gene imprinting. We discovered an unexpected role for DNA methylation in regulation of the Arabidopsis thaliana immune system. Profiling the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid (SA) hormone revealed numerous stress-induced differentially methylated regions (DMRs), many of which were intimately associated with differentially expressed genes. In response to SA, transposon-associated DMRs, which were accompanied by up-regulation of 21-nucleotide small interfering RNAs, were often coupled to transcriptional changes of the transposon or proximal genes. Thus, dynamic DNA methylation within repetitive sequences or transposons can regulate nearby genes in response to salicylic acid stress.
2012-05-15 | E-MTAB-4226 | biostudies-arrayexpress
Project description:DNA methylation is critical for development and is strongly associated with gene regulation. Variation in the DNA methylome between closely related species may reveal unique functional adaptation. We have implemented a novel inter-primate DNA methylation genome-wide analysis between human, chimpanzee and rhesus macaque to identify human species-specific Differentially Methylated Regions (human s-DMRs) in orthologous loci. We analysed the peripheral blood cell DNA methylomes of these primates and identified 22,758 hypomethylated and 15,858 hypermethylated human s-DMRs. These s-DMRs are globally enriched within weak promoter, enhancer and transcribed regions via comparison with ChromHMM segmentation. Human s-DMRs, (both hypo- and hypermethylated) are found to be more prevalent in CpG Island shores than within the islands themselves (?2 P = 1.80 x 10-32). Examining human-specific Transcription Factor Binding Site motif change within CpG islands, we show gain and loss, in hypomethylated and hypermethylated s-DMRs, respectively, of CTCF motifs. Epigenetically the most divergent human-specific locus was the immunological Leukotriene B4 receptor (LTB4R, aka BLT1 receptor), due to collocating hypomethylated s-DMRs within the promoter CpG island and shore, as well as inverse increased gene body methylation. This gene is vital in host immune responses and associated with the pathogenesis of a wide range of human inflammatory diseases. This finding was supported by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Functional investigation of the consequences of these epigenetic differences identified this receptor to have increased expression, and have a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
2014-02-01 | GSE48942 | GEO
Project description:<p><b>Background</b>: Circulating cell free (ccf) fetal DNA has enabled non-invasive prenatal fetal aneuploidy testing without direct discrimination of the genetically distinct maternal and fetal DNA. Current testing may be improved by specifically enriching the sample material for fetal DNA. DNA methylation may allow for such a separation of DNA and thus support additional clinical opportunities; however, this depends on knowledge of the methylomes of ccf DNA and its cellular contributors.</p> <p><b>Results</b>: Whole genome bisulfite sequencing was performed on a set of unmatched samples including ccf DNA from 8 non-pregnant (NP) and 7 pregnant female donors and genomic DNA from 7 buffy coat and 5 placenta samples. We found CpG cytosines within longer fragments were more likely to be methylated, linking DNA methylation and fragment size in ccf DNA. Comparison of the methylomes of placenta and NP ccf DNA revealed many of the 51,259 identified differentially methylated regions (DMRs) were located in domains exhibiting consistent placenta hypomethylation across millions of consecutive bases, regions we termed placenta hypomethylated domains. DMRs identified when comparing placenta to NP ccf DNA were recapitulated in pregnant ccf DNA, confirming the ability to detect differential methylation in ccf DNA mixtures.</p> <p><b>Conclusions</b>: We generated methylome maps for four sample types at single base resolution, identified a link between DNA methylation and fragment length in ccf DNA, identified DMRs between sample groups, and uncovered the presence of megabase-size placenta hypomethylated domains. Furthermore, we anticipate these results to provide a foundation to which future studies using discriminatory DNA methylation may be compared.</p>
| phs000846 | dbGaP
Project description:DNA methylation at the 5-postion of cytosine (5mC) is a well-established epigenetic modification which regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family is able to oxidize 5mC to 5-hydroxmethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer. We found that 5hmC is significantly enriched in CpG island (CGI) shores while depleted in CGS themselves, in particular at active genes, resulting in a 5hmC but not 5mC bimodal distribution around CGI corresponding to H3K4me1 marks. Hydroxymethylation on promoters, gene bodies, and transcription termination regions showed strong positive correlation with gene expression within and across tissues, suggesting that 5hmC is a mark of active genes and could play a role gene expression mediated by DNA demethylation. Comparative analysis of methylomes and hydroxymethylomes at differentially methylated regions (DMRs) revealed that 5hmC is significantly enriched in both tissue specific DMRs (t-DMRs) and cancer specific DMRs (c-DMRs), and 5hmC is negatively correlated with methylation changes, particularly in non-CGI associated DMRs. Analysis of differentially methylated regions (DMRs) in normal and tumor tissues revealed that gain or loss of 5hmC negatively correlated with changes in 5mC, especially on non-CGI associated DMRs, suggesting a profound role for hydroxymethylation in regulation of dynamic DNA demethylation. Together these findings indicate that changes in 5mC as well as in 5hmC and coupled to H3K4me1 correspond to differential gene expression in tissues and matching tumors, revealing an intricate gene expression regulation through interplay of methylome, hydroxymethylome, and histone modifications.
2016-10-05 | GSE70090 | GEO
Project description:DNA methylation at the 5-postion of cytosine (5mC) is a well-established epigenetic modification which regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family is able to oxidize 5mC to 5-hydroxmethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer. We found that 5hmC is significantly enriched in CpG island (CGI) shores while depleted in CGS themselves, in particular at active genes, resulting in a 5hmC but not 5mC bimodal distribution around CGI corresponding to H3K4me1 marks. Hydroxymethylation on promoters, gene bodies, and transcription termination regions showed strong positive correlation with gene expression within and across tissues, suggesting that 5hmC is a mark of active genes and could play a role gene expression mediated by DNA demethylation. Comparative analysis of methylomes and hydroxymethylomes at differentially methylated regions (DMRs) revealed that 5hmC is significantly enriched in both tissue specific DMRs (t-DMRs) and cancer specific DMRs (c-DMRs), and 5hmC is negatively correlated with methylation changes, particularly in non-CGI associated DMRs. Analysis of differentially methylated regions (DMRs) in normal and tumor tissues revealed that gain or loss of 5hmC negatively correlated with changes in 5mC, especially on non-CGI associated DMRs, suggesting a profound role for hydroxymethylation in regulation of dynamic DNA demethylation. Together these findings indicate that changes in 5mC as well as in 5hmC and coupled to H3K4me1 correspond to differential gene expression in tissues and matching tumors, revealing an intricate gene expression regulation through interplay of methylome, hydroxymethylome, and histone modifications.
2016-10-05 | GSE70089 | GEO
Project description:Genomic imprinting is a form of epigenetic regulation that results in expression of either the maternally or paternally inherited allele of a subset of genes. Imprinted loci contain differentially methylated regions (DMRs) where cytosine methylation marks one of the parental alleles, providing cis-acting regulatory elements that influence the allelic expression of surrounding genes, however to date the total number of imprinted loci within the human genome is unknown. To characterize known imprinted DMRS and identify novel imprinted loci we have performed whole-genome bisulphite sequencing and high-resolution DNA methylation array analysis of healthy tissues. Sequencing of bisulfite converted DNA analysis of normal brain (white matter), liver and term placenta tissue
2013-12-28 | E-GEOD-46698 | biostudies-arrayexpress
Project description:Genomic imprinting is a form of epigenetic regulation that results in expression of either the maternally or paternally inherited allele of a subset of genes. Imprinted loci contain differentially methylated regions (DMRs) where cytosine methylation marks one of the parental alleles, providing cis-acting regulatory elements that influence the allelic expression of surrounding genes, however to date the total number of imprinted loci within the human genome is unknown. To characterize known imprinted DMRS and identify novel imprinted loci we have performed whole-genome bisulphite sequencing and high-resolution DNA methylation array analysis of healthy tissues. Sequencing of bisulfite converted DNA and array based analysis of normal tissues, human embryonic stem cells, androgenetic hydatidiform moles and leukocytes from reciprocal genome-wide uniparental disomies.
2013-12-28 | E-GEOD-52576 | biostudies-arrayexpress