Inactive or moderately active human promoters are enriched for inter-individual epialleles
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE46220 | GEO | 2013/04/22
SECONDARY ACCESSION(S): PRJNA198097
REPOSITORIES: GEO
Similar Datasets
Project description:Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information.First, in a small sample set, we demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable over at least 2 years. Then, we show that iiDMRs are associated with changes in chromatin state as measured by inter-individual differences in histone variant H2A.Z levels. However, the correlation of promoter iiDMRs with gene expression is negligible and not improved by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for housekeeping genes, and either depleted for H3K4me3/enriched for H3K27me3 or lacking both these marks in human embryonic stem cells. The preferential enrichment of iiDMRs at regions of relative transcriptional inactivity validates in a larger independent cohort, and is reminiscent of observations previously made for promoters that undergo hypermethylation in various cancers, in vitro cell culture and ageing.Our work identifies potential key features of epiallelic variation in humans, including temporal stability of non-genetically determined epialleles, and concomitant perturbations of chromatin state. Furthermore, our work suggests a novel mechanistic link among inter-individual epialleles observed in the context of normal variation, cancer and ageing.
| S-EPMC4053860 | biostudies-other
Project description:We first demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable for at least two years. Then, we show that iiDMRS are associated with concomitant changes in chromatin state as measured by inter-individual differences in the levels of the histone variant H2A.Z. However, the correlation of promoter iiDMRs with gene expression is negligible and this correlation is not improved even by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for house keeping genes, and either depleted for H3K4me3/enriched for H3K27me3, or lacking both these marks in human embryonic stem cells. These findings validate in an independent cohort. Interestingly, the key features of iiDMRs are reminiscent of those previously observed for promoters that undergo hyper-methylation in various cancers, in vitro cell culture, and human chronological ageing.
2013-04-22 | GSE46168 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-04-22 | E-GEOD-46220 | biostudies-arrayexpress
Project description:We first demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable for at least two years. Then, we show that iiDMRS are associated with concomitant changes in chromatin state as measured by inter-individual differences in the levels of the histone variant H2A.Z. However, the correlation of promoter iiDMRs with gene expression is negligible and this correlation is not improved even by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for house keeping genes, and either depleted for H3K4me3/enriched for H3K27me3, or lacking both these marks in human embryonic stem cells. These findings validate in an independent cohort. Interestingly, the key features of iiDMRs are reminiscent of those previously observed for promoters that undergo hyper-methylation in various cancers, in vitro cell culture, and human chronological ageing.
2013-04-22 | GSE46217 | GEO
Project description:We first demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable for at least two years. Then, we show that iiDMRS are associated with concomitant changes in chromatin state as measured by inter-individual differences in the levels of the histone variant H2A.Z. However, the correlation of promoter iiDMRs with gene expression is negligible and this correlation is not improved even by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for house keeping genes, and either depleted for H3K4me3/enriched for H3K27me3, or lacking both these marks in human embryonic stem cells. These findings validate in an independent cohort. Interestingly, the key features of iiDMRs are reminiscent of those previously observed for promoters that undergo hyper-methylation in various cancers, in vitro cell culture, and human chronological ageing. H2A.z ChIP-seq, RNA-seq, and DNA methylation data (submitted separately) were collected for five normal individuals. T21/T22 and T31/T32 are monozygotic twins.
2013-04-22 | E-GEOD-46217 | biostudies-arrayexpress
Project description:We first demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable for at least two years. Then, we show that iiDMRS are associated with concomitant changes in chromatin state as measured by inter-individual differences in the levels of the histone variant H2A.Z. However, the correlation of promoter iiDMRs with gene expression is negligible and this correlation is not improved even by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for house keeping genes, and either depleted for H3K4me3/enriched for H3K27me3, or lacking both these marks in human embryonic stem cells. These findings validate in an independent cohort. Interestingly, the key features of iiDMRs are reminiscent of those previously observed for promoters that undergo hyper-methylation in various cancers, in vitro cell culture, and human chronological ageing. DNA Methylation, H2A.z ChIP-seq, RNA-seq (submitted) separately were collected for five normal individuals (samples with "T" prefixes). T21/T22 and T31/T32 are monozygotic twins. Further DNA methylation data was collected from and additional two pairs of MZ twins with technical replication (samples with "C" prefixes - the three digits are pair number, individual number, and replicate number). Bisulphite converted DNA was hybridised to the Illumina Infinium 450k Human Methylation Beadchip
2013-04-22 | E-GEOD-46168 | biostudies-arrayexpress
Project description:LINE-1 repeats account for ~17% of the human genome. Little is known about their individual methylation patterns, because their repetitive, almost identical sequences make them difficult to be individually targeted. Here, we used bisulfite conversion to study methylation at individual LINE-1 repeats. The loci studied included 39 X-linked loci and 5 autosomal loci. On the X chromosome in women, we found statistically significant less methylation at almost all L1Hs compared with men. Methylation at L1P and L1M did not correlate with the inactivation status of the host DNA, while the majority of L1Hs that were possible to be studied lie in inactivated regions. To investigate whether the male-female differences at L1Hs on the X are linked to the inactivation process itself rather than to a mere influence of gender, we analyzed six of the L1Hs loci on the X chromosome in Turners and Klinefelters which have female and male phenotype, respectively, but with reversed number of X chromosomes. We could confirm that all samples with two X chromosomes are hypomethylated at the L1Hs loci. Therefore, the inactive X is hypomethylated at L1Hs; the latter could play an exclusive role in the X chromosome inactivation process. At autosomal L1Hs, methylation levels showed a correlation tendency between methylation level and genome size, with higher methylation observed at most loci in individuals with one X chromosome and the lowest in XXY individuals. In summary, loci-specific LINE-1 methylation levels show considerable plasticity and depend on genomic position and constitution.
| S-EPMC3235015 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-02-04 | GSE38242 | GEO
Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. In order to characterize epigenetic changes that accompany this process, we measured DNA methylation levels in both 45,X Turner syndrome patients, who carry a single active X chromosome (Xa) and normal 46,XX females, who carry one Xa and one inactive X (Xi). Methylated DNA was immunoprecipitated and hybridized to tiling oligonucleotide arrays, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands. While the majority of CpG islands show increased methylation levels on the Xi, XCI results in reduced methylation at ~20% of CpG islands. Both intra- and inter-genic CpG islands are epigenetically modified, with the biggest increase in methylation occuring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI have low levels of promoter methylation, while genes that undergo polymorphic silencing show intermediate increases in methylation proportionate to their frequency of inactivation. Thus promoter methylation and susceptibility to XCI are correlated. We observed a global correlation between CpG island methylation and the evolutionary age of different X chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We utilized our epigenetic map to predict both novel genes escaping XCI, and to identify sequence features that may contribute to the XCI process. Finally, as our study included Turner syndrome patients with single X chromosomes of both maternal and paternal origin we searched for parent-of-origin specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides the first epigenetic profile of active and inactive X chromosomes, giving novel insights into the phenomenon of dosage compensation.
2010-07-20 | GSE22551 | GEO
Project description:We report the application of single molecule-based sequencing technology in combination with MBD affinity purifcation (MAP-seq) to generate methylation maps in a panel of human brain samples. Here we assay the methylation status of the human genome in eight distinct brain regions from three individuals in addition to a further thirty six hippocampal samples. The cerebellum was a consistent outlier compared to all other regions, showing over 16,000 differentially methylated regions (DMRs). Unexpectedly, the sequence properties of hypo- and hyper- methylated domains in cerebellum were distinct. In contrast we found very few DMRs that could distinguish between regions of the cortex, limbic system and brain stem. Inter-individual DMRs were readily detectable, however with the exception of cerebellum, DNA methylation patterns are more similar between different brain regions from the same individual, than they are for a single brain region between different individuals.
2014-12-01 | GSE50960 | GEO