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DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines.

Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK - Genome Biol. (2011)

Bottom Line: The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall.As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes.Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. jordana@well.ox.ac.uk

ABSTRACT

Background: DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available.

Results: Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG-sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%. The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall. As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes. Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels.

Conclusions: Our results demonstrate a strong genetic component to inter-individual variation in DNA methylation profiles. Furthermore, there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes.

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Related in: MedlinePlus

Distribution of methylation patterns across the genome. (a) Methylation patterns for CpG-sites on autosomes, X-chromosome, and in the vicinity of imprinted genes. Methylation values are plotted for 77 individuals at 21,289 autosomal CpG-sites (left), for 43 females at 997 CpG-sites on the X-chromosome (middle), and for 77 individuals at 153 CpG-sites in 33 imprinted genes (right). (b) Methylation levels with respect to the TSS (negative distances are upstream from the TSS), where the line represents running median levels in sliding windows of 300 bp. (c) Correlations in methylation levels for all pair-wise CpG-sites (black), and for CpG-sites where both probes are in the same CGI (red), or where at least one probe is outside of CGIs (blue). Lines indicate smoothed spline fits of the mean rank pairwise correlation between CpG-sites in 100 bp windows, weighted by the number of probe pairs. (d) Methylation levels inside and outside of annotation categories, including CpG Islands (CGIs) for probes within 100 bp of the TSS, and histone modifications and transcription factor (TF) binding sites for all probes (see Additional file 1).
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Figure 1: Distribution of methylation patterns across the genome. (a) Methylation patterns for CpG-sites on autosomes, X-chromosome, and in the vicinity of imprinted genes. Methylation values are plotted for 77 individuals at 21,289 autosomal CpG-sites (left), for 43 females at 997 CpG-sites on the X-chromosome (middle), and for 77 individuals at 153 CpG-sites in 33 imprinted genes (right). (b) Methylation levels with respect to the TSS (negative distances are upstream from the TSS), where the line represents running median levels in sliding windows of 300 bp. (c) Correlations in methylation levels for all pair-wise CpG-sites (black), and for CpG-sites where both probes are in the same CGI (red), or where at least one probe is outside of CGIs (blue). Lines indicate smoothed spline fits of the mean rank pairwise correlation between CpG-sites in 100 bp windows, weighted by the number of probe pairs. (d) Methylation levels inside and outside of annotation categories, including CpG Islands (CGIs) for probes within 100 bp of the TSS, and histone modifications and transcription factor (TF) binding sites for all probes (see Additional file 1).

Mentions: Distinct patterns of methylation were observed for CpG-sites located on the autosomes, X-chromosome, and in the vicinity of imprinted genes (Figure 1a). The majority (71.4%) of autosomal CpG-sites were primarily unmethylated (observed fraction of methylation <0.3), 15.6% were hemi-methylated (fraction of methylation was between 0.3 and 0.7), and 13% were methylated. As expected, these patterns were consistent with previously observed lower levels of methylation near promoters relative to genome-wide levels [4,31]. We did not find evidence for sex-specific autosomal methylation patterns, consistent with a previous report [4]. In contrast, CpG-sites on the X-chromosome exhibited highly significant sex-specific differences (Figure S2) with hemi-methylated patterns in females that were consistent with X-chromosome inactivation. A similar hemi-methylation peak was observed for CpG-sites located near the transcription start sites (TSSs) of known autosomal imprinted genes in the entire sample.


DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines.

Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK - Genome Biol. (2011)

Distribution of methylation patterns across the genome. (a) Methylation patterns for CpG-sites on autosomes, X-chromosome, and in the vicinity of imprinted genes. Methylation values are plotted for 77 individuals at 21,289 autosomal CpG-sites (left), for 43 females at 997 CpG-sites on the X-chromosome (middle), and for 77 individuals at 153 CpG-sites in 33 imprinted genes (right). (b) Methylation levels with respect to the TSS (negative distances are upstream from the TSS), where the line represents running median levels in sliding windows of 300 bp. (c) Correlations in methylation levels for all pair-wise CpG-sites (black), and for CpG-sites where both probes are in the same CGI (red), or where at least one probe is outside of CGIs (blue). Lines indicate smoothed spline fits of the mean rank pairwise correlation between CpG-sites in 100 bp windows, weighted by the number of probe pairs. (d) Methylation levels inside and outside of annotation categories, including CpG Islands (CGIs) for probes within 100 bp of the TSS, and histone modifications and transcription factor (TF) binding sites for all probes (see Additional file 1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3091299&req=5

Figure 1: Distribution of methylation patterns across the genome. (a) Methylation patterns for CpG-sites on autosomes, X-chromosome, and in the vicinity of imprinted genes. Methylation values are plotted for 77 individuals at 21,289 autosomal CpG-sites (left), for 43 females at 997 CpG-sites on the X-chromosome (middle), and for 77 individuals at 153 CpG-sites in 33 imprinted genes (right). (b) Methylation levels with respect to the TSS (negative distances are upstream from the TSS), where the line represents running median levels in sliding windows of 300 bp. (c) Correlations in methylation levels for all pair-wise CpG-sites (black), and for CpG-sites where both probes are in the same CGI (red), or where at least one probe is outside of CGIs (blue). Lines indicate smoothed spline fits of the mean rank pairwise correlation between CpG-sites in 100 bp windows, weighted by the number of probe pairs. (d) Methylation levels inside and outside of annotation categories, including CpG Islands (CGIs) for probes within 100 bp of the TSS, and histone modifications and transcription factor (TF) binding sites for all probes (see Additional file 1).
Mentions: Distinct patterns of methylation were observed for CpG-sites located on the autosomes, X-chromosome, and in the vicinity of imprinted genes (Figure 1a). The majority (71.4%) of autosomal CpG-sites were primarily unmethylated (observed fraction of methylation <0.3), 15.6% were hemi-methylated (fraction of methylation was between 0.3 and 0.7), and 13% were methylated. As expected, these patterns were consistent with previously observed lower levels of methylation near promoters relative to genome-wide levels [4,31]. We did not find evidence for sex-specific autosomal methylation patterns, consistent with a previous report [4]. In contrast, CpG-sites on the X-chromosome exhibited highly significant sex-specific differences (Figure S2) with hemi-methylated patterns in females that were consistent with X-chromosome inactivation. A similar hemi-methylation peak was observed for CpG-sites located near the transcription start sites (TSSs) of known autosomal imprinted genes in the entire sample.

Bottom Line: The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall.As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes.Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. jordana@well.ox.ac.uk

ABSTRACT

Background: DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available.

Results: Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG-sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%. The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall. As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes. Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels.

Conclusions: Our results demonstrate a strong genetic component to inter-individual variation in DNA methylation profiles. Furthermore, there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes.

Show MeSH
Related in: MedlinePlus