Department of Biology, Bryn Mawr College, 101 N. Merion Avenue, Bryn Mawr, PA 19010-2899, USA.
Epigenetics Chromatin. 2014 May 29;7:9. doi: 10.1186/1756-8935-7-9. eCollection 2014.
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. 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.
In 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.
These 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.
印迹基因的亲本等位基因上 DNA 甲基化的差异分布将等位基因彼此区分开来，并决定其亲本来源特异性表达模式。虽然主要印迹控制区域的差异 DNA 甲基化通过配子遗传，但在胚胎发育过程中，在二级位点会获得额外的等位基因特异性 DNA 甲基化，这在基因组印迹的维持中发挥作用。这种在二级位点建立体细胞 DNA 甲基化的确切机制尚未明确定义，并且可能因印迹簇中不同基因的这些位点的甲基化获得时间不同而有所不同。
在这项研究中，我们表明，在单个印迹簇内的多个位点上，体细胞 DNA 甲基化的获得时间也存在差异。父本等位基因特异性 DNA 甲基化在 Dlk1 和 Gtl2 差异甲基化区域 (DMR) 的附-linked 后植入发育的相似阶段最初被获得。相比之下，与 Gtl2-DMR 不同，母本 Dlk1-DMR 在成年组织中获得 DNA 甲基化。
这些数据表明，Dlk1/Gtl2 印迹簇的 DNA 甲基化获得具有可变性。我们进一步发现，Dlk1 差异甲基化区域显示出低的 DNA 甲基化保真度，这表现为大约三分之一的甲基化 CpG 二联体存在半甲基化。我们假设，与主要印迹控制区域相比，次级差异甲基化位点的 DNA 甲基化维持效率可能较低。
