Abstract
One of the best studied read-outs of epigenetic change is the differential expression of imprinted genes, controlled by differential methylation of imprinted control regions (ICRs). To address the impact of genotype on the epigenome, we performed a detailed study in 128 pairs of monozygotic (MZ) and 128 pairs of dizygotic (DZ) twins, interrogating the DNA methylation status of the ICRs of IGF2, H19, KCNQ1, GNAS and the non-imprinted gene RUNX1. While we found a similar overall pattern of methylation between MZ and DZ twins, we also observed a high degree of variability in individual CpG methylation levels, notably at the H19/IGF2 loci. A degree of methylation plasticity independent of the genome sequence was observed, with both local and regional CpG methylation changes, discordant between MZ and DZ individual pairs. However, concordant gains or losses of methylation, within individual twin pairs were more common in MZ than DZ twin pairs, indicating that de novo and/or maintenance methylation is influenced by the underlying DNA sequence. Specifically, for the first time we showed that the rs10732516 [A] polymorphism, located in a critical CTCF binding site in the H19 ICR locus, is strongly associated with increased hypermethylation of specific CpG sites in the maternal H19 allele. Together, our results highlight the impact of the genome on the epigenome and demonstrate that while DNA methylation states are tightly maintained between genetically identical and related individuals, there remains considerable epigenetic variation that may contribute to disease susceptibility.
Highlights
Genetic polymorphisms are heritable alterations in the DNA sequence and contribute to phenotypic variation, and sometimes to disease susceptibility, through effects on gene expression and function
We examined in detail the DNA methylation status of four imprinting control regions (H19-imprinted control regions (ICRs), IGF2-differentially methylated regions (DMRs), KvDMR and NEPAS-ICR) located both in clusters and on different chromosomes in a sample of 128 pairs of monozygotic and 128 pairs of dizygotic twins, to address potential in cis and/or in trans methylation variance in identical and related individuals
For both the MZ and DZ pairs we found that H19-ICR and IGF2-DMR DNA methylation levels displayed a considerable degree of variation, far greater than KvDMR, NESPAS-ICR or the RUNX1 promoter
Summary
Genetic polymorphisms are heritable alterations in the DNA sequence and contribute to phenotypic variation, and sometimes to disease susceptibility, through effects on gene expression and function. The best documented imprinting cluster harbours the genes IGF2 and H19, and is located on chromosome 11p15.5 in humans (Figure 1A) [2] These adjacent genes are reciprocally imprinted; the potential growth factor IGF2 is paternally expressed, whereas for the noncoding RNA H19, the maternal allele is active [3,4]. A second imprinting domain is located centromeric to the IGF2/H19 locus, referred to as KCNQ1 (Figure 1A) This domain contains several maternally expressed genes and a single paternally expressed transcript, KCNQ1OT1. Disruption of the differential methylation of KvDMR is observed in over half of the cases of the congenital overgrowth disorder called BeckwithWiedemann syndrome (BWS) [11,12,13], as well as in colorectal cancer tissue specimens [14] Another example of clustering of imprinted genes in the human genome is the GNAS locus on 20q13.32. Disruption of the (regulation of the) GNAS locus can result in various human disorders, including pseudohypoparathyroidism and some tumours of different origin [17]
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