Regions of common inter-individual DNA methylation differences in human monocytes: genetic basis and potential function

Abstract

BackgroundThere 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.ResultsWe 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.ConclusionsAllele-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-017-0144-2) contains supplementary material, which is available to authorized users.

Epigenetic regulation of gene expression in Chinese Hamster Ovary cells in response to the changing environment of a batch culture

“…The highest significant ( p < 0.01) correlation is observed for H3K36me3‐E4 marks (Supporting Information Figure 7a). Read distribution for hyperacetylation of different phase‐wise comparisons (ES, ED, and SD) shows that the genome has more hyperacetylated sites in exponential phase (Supporting Information Figure 8), which agrees well with the higher transcriptional changes in this phase (Schröder et al, ; Sharp et al, ). Moreover, out of 1,397 DE coding genes, 986 genes had H3K36me3‐E4 within their gene body, but only 731 had H3K4me3‐E9,10 and 721 had H3K27ac‐E9,10 around the TSS, and only 647 genes were found to have all three active chromatin marks.…”

“…The top gene ontology terms enriched are tabulated under each cluster with classic Fisher values. CHO: Chinese Hamster Ovary [Color figure can be viewed at wileyonlinelibrary.com]that the genome has more hyperacetylated sites in exponential phase (Supporting InformationFigure 8), which agrees well with the higher transcriptional changes in this phase(Schröder et al, 2017;Sharp et al, 2011). Moreover, out of 1,397 DE coding genes, 986 genes had H3K36me3-E4 within their gene body, but only 731 had H3K4me3-E9,10 and 721 had H3K27ac-E9,10 around the TSS, and only 647 genes were found to have all three active chromatin marks.…”

Targeted bisulfite sequencing: A novel tool for the assessment of DNA methylation with high sensitivity and increased coverage

“…Second, DNA was extracted from saliva, which represents a heterogeneous tissue, and introduces a potential bias into the analysis (Jones et al, 2018;Kumsta, 2019). Third, individual genotype influencing individual DNA methylation signatures cannot be excluded (Gertz et al, 2011;Schroder et al, 2017). Fourth, the investigated cohort was rather small (Heijmans and Mill, 2012) and last but not least, differences in DNA methylation of way below 1 % are unlikely to be of biological significance (Heijmans and Mill, 2012;Matthijs et al, 2016).…”

Healthy ageing men have normal reproductive function but display germline-specific molecular changes

“…Sperm and blood DNA, respectively, from six "young" men (18-24 years) and six "old" men (61-71 years) were pooled at equimolar ratios. We used pooled DNA to minimize the effect of inter-individual DNA methylation differences (49)(50)(51). For each of the 4 pools, two shotgun libraries were generated.…”