Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns

Abstract

DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of gene-specific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

“…Figure 3 and Supporting Information Figure S2 show that single CpG methylation errors occur at low frequency (usually < 1%) at every CpG in all analyzed genes. The observed minor fluctuations in average methylation levels among neighboring CpGs in an overall hypomethylated promoter may reflect differences in chromatin structure rather than probabilistic events 32. To distinguish between stochastic noise and potentially relevant single CpG hypermethylation, we defined a threshold for each CpG in a given assay based on box plot analysis of control samples without epimutations: single CpG methylation values more than five times the interquartile range (IQR) away from the 75 th percentile were considered as abnormal.…”

Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs

“…Accompanied with the gene expression changes of Igf2, the methylation status of ICR and DMR2 also manifested similar alterations in the F1 and F3 generation. Theoretically, DNA methylation of imprinted gene should be 50% in somatic cells for its monoallelic expression, although the average methylation levels of DMR in healthy somatic tissues could be varied along with different genes or tissue types (Schneider et al, 2010). The majority of clones manifested hyper/ hypomethylated trend in the ICR/DMR2 in the F1 and F3 TCDD lineages, indicating that both the maternal and paternal alleles might be affected during embryonic development.…”

GWAS of DNA Methylation Variation Within Imprinting Control Regions Suggests Parent-of-Origin Association

“…Dynamic changes can result either from carefully directed epigenetic reprogramming processes during development or from environmental exposure, aging or stochastic factors (Horsthemke, 2006;Schanen, 2006;Schneider et al, 2010;Siegmund et al, 2007;Waterland & Jirtle, 2003). While the dynamic nature of the epigenome is widely acknowledged, little is known about what drives this variation.…”