Regions of common inter-individual DNA methylation differences in human monocytes.
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ABSTRACT:
PROVIDER: EGAS00001002265 | EGA |
REPOSITORIES: EGA
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Project description:Background: DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results: We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. Via eQTL analysis with microarray data combined with mapping of allelic expression regions, we obtained a set of 2770 regions mappable in cis to sequence variation. In 9.5% of these expressed regions, an associated SNP was also a methylation QTL. Methylation and gene expression are often correlated without direct discernible involvement of sequence variation, but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase I hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion: Our results indicate a wide variety of relationships between gene expression, DNA methylation and sequence variation in untransformed adult human fibroblasts, with considerable involvement of chromatin features. We note particularly high levels of variation and correlation in DNA methylation and gene expression at key developmental loci, with little discernible involvement of sequence variation.
2013-12-13 | GSE53243 | GEO
Project description:Background DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. However, only 5% of those mappable CpG sites also have methylation levels that correlate in cis with a gene's expression level. Methylation and gene expression are often correlated but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion Our results indicate strong relationships between gene expression and DNA methylation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and relatively modest involvement of sequence variation.
2013-12-11 | GSE52442 | GEO
Project description:Background: DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results: We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. Via eQTL analysis with microarray data combined with mapping of allelic expression regions, we obtained a set of 2770 regions mappable in cis to sequence variation. In 9.5% of these expressed regions, an associated SNP was also a methylation QTL. Methylation and gene expression are often correlated without direct discernible involvement of sequence variation, but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase I hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion: Our results indicate a wide variety of relationships between gene expression, DNA methylation and sequence variation in untransformed adult human fibroblasts, with considerable involvement of chromatin features. We note particularly high levels of variation and correlation in DNA methylation and gene expression at key developmental loci, with little discernible involvement of sequence variation. Ref-8 Gene Expression Data for human primary fibroblast lines
2013-12-13 | E-GEOD-53243 | biostudies-arrayexpress
Project description:Background DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. However, only 5% of those mappable CpG sites also have methylation levels that correlate in cis with a gene's expression level. Methylation and gene expression are often correlated but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion Our results indicate strong relationships between gene expression and DNA methylation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and relatively modest involvement of sequence variation.
2013-12-10 | GSE52025 | GEO
Project description:Background DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. However, only 5% of those mappable CpG sites also have methylation levels that correlate in cis with a gene's expression level. Methylation and gene expression are often correlated but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion Our results indicate strong relationships between gene expression and DNA methylation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and relatively modest involvement of sequence variation. 98 human skin fibroblast samples obtained from Coriell and McGill Cellbank, genotypes were obtained using Illumina HumanOmni 1M Beadchips.
2013-12-11 | E-GEOD-52442 | biostudies-arrayexpress
Project description:Background DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. However, only 5% of those mappable CpG sites also have methylation levels that correlate in cis with a gene's expression level. Methylation and gene expression are often correlated but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion Our results indicate strong relationships between gene expression and DNA methylation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and relatively modest involvement of sequence variation. 62 human skin fibroblast samples obtained from Coriell and McGill Cellbank, bisulfite converted DNA was hybridized to the Illumina Infinium 450K chip.
2013-12-10 | E-GEOD-52025 | biostudies-arrayexpress
Project description:There is increasing evidence for inter-individual methylation differences at CpG dinucleotides in the human genome, but the regional extent and function of these differences have not yet been studied in detail. For identifying regions of common methylation differences, we used whole genome bisulfite sequencing data of monocytes from five donors and a novel bioinformatic strategy.We identified 157 differentially methylated regions (DMRs) with four or more CpGs, almost none of which has been described before. The DMRs fall into different chromatin states, where methylation is inversely correlated with active, but not repressive histone marks. However, methylation is not correlated with the expression of associated genes. High-resolution single nucleotide polymorphism (SNP) genotyping of the five donors revealed evidence for a role of cis-acting genetic variation in establishing methylation patterns. To validate this finding in a larger cohort, we performed genome-wide association studies (GWAS) using SNP genotypes and 450k array methylation data from blood samples of 1128 individuals. Only 30/157 (19%) DMRs include at least one 450k CpG, which shows that these arrays miss a large proportion of DNA methylation variation. In most cases, the GWAS peak overlapped the CpG position, and these regions are enriched for CREB group, NF-1, Sp100 and CTCF binding motifs. In two cases, there was tentative evidence for a trans-effect by KRAB zinc finger proteins.Allele-specific DNA methylation occurs in discrete chromosomal regions and is driven by genetic variation in cis and trans, but in general has little effect on gene expression.
| S-EPMC5530492 | biostudies-literature
Project description:Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52–79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intra-individual differences. This will create substantial challenges in humans, where multiple tissues are not readily available.
2009-05-19 | GSE8356 | GEO
Project description:Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52–79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intra-individual differences. This will create substantial challenges in humans, where multiple tissues are not readily available.
2009-05-19 | GSE8355 | GEO
Project description:Background DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Results We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5kb. However, only 5% of those mappable CpG sites also have methylation levels that correlate in cis with a gene's expression level. Methylation and gene expression are often correlated but not always in the expected direction (negative for promoter CpGs, positive for gene body CpGs). Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific histone marks or DNase hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants. Conclusion Our results indicate strong relationships between gene expression and DNA methylation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and relatively modest involvement of sequence variation.
2014-01-25 | GSE54373 | GEO