Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50853 | GEO | 2013/09/14
SECONDARY ACCESSION(S): PRJNA219172
REPOSITORIES: GEO
Similar Datasets
Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG-island-containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non-neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells.
| S-EPMC3874157 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-09-14 | E-GEOD-50853 | biostudies-arrayexpress
Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG island–containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non– neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells. Genomic DNA was isolated from FACS-sorted human brain neuronal and nonneuronal nuclei. DNA was bisulfite converted and hybridised to the Illumina Infinium 450K Human Methylation Beadchip array. Six subjects in two technical replicate expriments were analyzed.
2013-09-13 | E-GEOD-50798 | biostudies-arrayexpress
Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG island–containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non– neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells.
2013-09-13 | GSE50798 | GEO
Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG islandM-bM-^@M-^Scontaining promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and nonneuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells. Extended Reduced Representation Bisulfite Sequencing (ERRBS) was performed on genomic DNA to validate the Infinium HM450K DNA methylation data (Kozlenkov et. al., 2013, Nucleic Acids Research, accepted for publication).
2013-09-14 | E-GEOD-50852 | biostudies-arrayexpress
Project description:We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG island–containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and nonneuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells.
2013-09-14 | GSE50852 | GEO
Project description:TET2 enzymatically converts 5-methylcytosine to 5-hydroxymethylcytosine as well as other covalently modified cytosines and its mutations are common in myeloid leukemia. However, the exact mechanism and the extent to which TET2 mutations affect DNA methylation remain in question. Here, we report on DNA methylomes in TET2 wild-type (TET2-WT) and mutant (TET2-MT) cases of chronic myelomonocytic leukemia (CMML). We analyzed 85,134 CpG sites [28,114 sites in CpG islands (CGI) and 57,020 in non-CpG islands (NCGI)]. TET2 mutations do not explain genome-wide differences in DNA methylation in CMML, and we found few and inconsistent differences at CGIs between TET2-WT and TET2-MT cases. In contrast, we identified 409 (0.71%) TET2-specific differentially methylated CpGs (tet2-DMCs) in NCGIs, 86% of which were hypermethylated in TET2-MT cases, suggesting a strikingly different biology of the effects of TET2 mutations at CGIs and NCGIs. DNA methylation of tet2-DMCs at promoters and nonpromoters repressed gene expression. Tet2-DMCs showed significant enrichment at hematopoietic-specific enhancers marked by H3K4me1 and at binding sites for the transcription factor p300. Tet2-DMCs showed significantly lower 5-hydroxymethylcytosine in TET2-MT cases. We conclude that leukemia-associated TET2 mutations affect DNA methylation at NCGI regions containing hematopoietic-specific enhancers and transcription factor-binding sites.
| S-EPMC4506197 | biostudies-literature
Project description:Methylation of cytosine is an epigenetic mark involved in the regulation of transcription, usually associated with transcriptional repression. In mammals, methylated cytosines are found predominantly in CpGs but in plants non-CpG methylation (in the CpHpG or CpHpH contexts, where H is A, C or T) is also present and is associated with the transcriptional silencing of transposable elements. In addition, CpG methylation is found in coding regions of active genes. In the absence of the demethylase of lysine 9 of histone 3 (IBM1), a subset of body-methylated genes acquires non-CpG methylation. This was shown to alter their expression and affect plant development. It is not clear why only certain body-methylated genes gain non-CpG methylation in the absence of IBM1 and others do not. Here we describe a link between CpG methylation and the establishment of methylation in the CpHpG context that explains the two classes of body-methylated genes. We provide evidence that external cytosines of CpCpG sites can only be methylated when internal cytosines are methylated. CpCpG sites methylated in both cytosines promote spreading of methylation in the CpHpG context in genes protected by IBM1. In contrast, CpCpG sites remain unmethylated in IBM1-independent genes and do not promote spread of CpHpG methylation.
| S-EPMC5397141 | biostudies-literature
Project description:BACKGROUND: A major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome-wide mutation profile. The rate of germ line mutation is considerably higher for cytosines at CpG sites than for any other nucleotide in the human genome, an increase commonly attributed to cytosine methylation at CpG sites. The CpG mutation rate, however, is not uniform across the genome and, as methylation levels have recently been shown to vary throughout the genome, it has been hypothesized that methylation status may govern variation in the rate of CpG mutation. RESULTS: Here, we use genome-wide methylation data from human sperm cells to investigate the impact of DNA methylation on the CpG substitution rate in introns of human genes. We find that there is a significant correlation between the extent of methylation and the substitution rate at CpG sites. Further, we show that the CpG substitution rate is positively correlated with non-CpG divergence, suggesting susceptibility to factors responsible for the general mutation rate in the genome, and negatively correlated with GC content. We only observe a minor contribution of gene expression level, while recombination rate appears to have no significant effect. CONCLUSIONS: Our study provides the first direct empirical support for the hypothesis that variation in the level of germ line methylation contributes to substitution rate variation at CpG sites. Moreover, we show that other genomic features also impact on CpG substitution rate variation.
| S-EPMC3218846 | biostudies-literature
Project description:A next generation bisulfite sequencing (NGBS) was used to study rDNA promoter methylation in human brain using postmortem samples of the parietal cortex. Qualitative analysis of patterns of CpG methylation was performed at the individual rDNA unit level. CpG site-specific differences in methylation frequency were observed with the core promoter harboring three out of four most methylated CpGs. Moreover, there was an overall trend towards co-methylation for all possible pairs of 26 CpG sites. The hypermethylated CpGs from the core promoter were also most likely to be co-methylated. Finally, although rare, non-CpG (CpH) methylation was detected at several sites with one of them confirmed using the PspGI-qPCR assay. Similar trends were observed in samples from control individuals as well as patients suffering of Alzheimer's disease (AD), mild cognitive impairment (MCI) or ataxia telangiectasia (AT). Taken together, while some methyl-CpG sites including those in the core promoter may have relatively greater inhibitory effect on rRNA transcription, co-methylation at multiple sites may be required for full and/or long lasting silencing of human rDNA.
| S-EPMC4934664 | biostudies-other