Abstract
BackgroundDifferential distribution of DNA methylation on the parental alleles of imprinted genes distinguishes the alleles from each other and dictates their parent of origin-specific expression patterns. While differential DNA methylation at primary imprinting control regions is inherited via the gametes, additional allele-specific DNA methylation is acquired at secondary sites during embryonic development and plays a role in the maintenance of genomic imprinting. The precise mechanisms by which this somatic DNA methylation is established at secondary sites are not well defined and may vary as methylation acquisition at these sites occurs at different times for genes in different imprinting clusters.ResultsIn this study, we show that there is also variability in the timing of somatic DNA methylation acquisition at multiple sites within a single imprinting cluster. Paternal allele-specific DNA methylation is initially acquired at similar stages of post-implantation development at the linked Dlk1 and Gtl2 differentially methylated regions (DMRs). In contrast, unlike the Gtl2-DMR, the maternal Dlk1-DMR acquires DNA methylation in adult tissues.ConclusionsThese data suggest that the acquisition of DNA methylation across the Dlk1/Gtl2 imprinting cluster is variable. We further found that the Dlk1 differentially methylated region displays low DNA methylation fidelity, as evidenced by the presence of hemimethylation at approximately one-third of the methylated CpG dyads. We hypothesize that the maintenance of DNA methylation may be less efficient at secondary differentially methylated sites than at primary imprinting control regions.
Highlights
Differential distribution of DNA methylation on the parental alleles of imprinted genes distinguishes the alleles from each other and dictates their parent of origin-specific expression patterns
The Dlk1-differentially methylated region (DMR) acquires paternal allele-specific DNA methylation during post-fertilization development Previous research illustrated that somatic mouse tissues exhibit paternal allele-specific DNA methylation at the Dlk1-DMR that is acquired after fertilization [5,14,15]
Our analysis of DNA methylation at the mouse Dlk1-DMR illustrates that the acquisition of paternal allele-specific DNA methylation initiates between 3.5 and 6.5 d.p.c., suggesting that epigenetic modifications across the Dlk1-Dio3 imprinting cluster may be coordinately regulated during post-implantation development
Summary
Differential distribution of DNA methylation on the parental alleles of imprinted genes distinguishes the alleles from each other and dictates their parent of origin-specific expression patterns. It has been proposed that the establishment of differential DNA methylation at secondary DMRs could serve as a mechanism for maintaining imprinted expression at developmental times when the primary imprinting control region is no longer functioning [6,7]. Support for this hypothesis comes from a recent study of DNA methylation and expression at the imprinted Gpr1-Zdbf locus at which the maternally methylated Gpr DMR functions as the gametic imprinting mark responsible for establishing paternal allele-specific expression while paternal allele-specific DNA methylation at the secondary Zdbf DMR is established after the onset of imprinted Zdbf expression [8]. While the exact mechanism responsible for the parental allele-specific acquisition of DNA methylation at secondary DMRs has not yet been determined, it is clear that there is a relationship between the epigenetic states at primary and secondary DMRs [9,10]
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