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首页> 外文期刊>Epigenetics & Chromatin >Hemimethylation of CpG dyads is characteristic of secondary DMRs associated with imprinted loci and correlates with 5-hydroxymethylcytosine at paternally methylated sequences
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Hemimethylation of CpG dyads is characteristic of secondary DMRs associated with imprinted loci and correlates with 5-hydroxymethylcytosine at paternally methylated sequences

机译：CpG dyads的半甲基化是继发性DMR的特征，与标记基因座相关，并与父本甲基化序列上的5-羟甲基胞嘧啶相关

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In mammals, the regulation of imprinted genes is controlled by differential methylation at imprinting control regions which acquire parent of origin-specific methylation patterns during gametogenesis and retain differences in allelic methylation status throughout fertilization and subsequent somatic cell divisions. In addition, many imprinted genes acquire differential methylation during post-implantation development; these secondary differentially methylated regions appear necessary to maintain the imprinted expression state of individual genes. Despite the requirement for both types of differentially methylated sequence elements to achieve proper expression across imprinting clusters, methylation patterns are more labile at secondary differentially methylated regions. To understand the nature of this variability, we analyzed CpG dyad methylation patterns at both paternally and maternally methylated imprinted loci within multiple imprinting clusters. We determined that both paternally and maternally methylated secondary differentially methylated regions associated with imprinted genes display high levels of hemimethylation, 29–49%, in comparison to imprinting control regions which exhibited 8–12% hemimethylation. To explore how hemimethylation could arise, we assessed the differentially methylated regions for the presence of 5-hydroxymethylcytosine which could cause methylation to be lost via either passive and/or active demethylation mechanisms. We found enrichment of 5-hydroxymethylcytosine at paternally methylated secondary differentially methylated regions, but not at the maternally methylated sites we analyzed in this study. We found high levels of hemimethylation to be a generalizable characteristic of secondary differentially methylated regions associated with imprinted genes. We propose that 5-hydroxymethylcytosine enrichment may be responsible for the variability in methylation status at paternally methylated secondary differentially methylated regions associated with imprinted genes. We further suggest that the high incidence of hemimethylation at secondary differentially methylated regions must be counteracted by continuous methylation acquisition at these loci.
机译：在哺乳动物中，印迹基因的调控是由印迹控制区域的差异甲基化控制的，该区域在配子发生过程中获得起源特定甲基化模式的母体，并在受精和随后的体细胞分裂过程中保留等位基因甲基化状态的差异。另外，许多印迹基因在植入后发育过程中获得差异甲基化。这些次级差异甲基化区域似乎对于维持单个基因的印迹表达状态是必需的。尽管需要两种类型的差异甲基化序列元件才能在整个印迹簇上实现正确表达，但甲基化模式在二级差异甲基化区域更不稳定。为了了解这种可变性的本质，我们分析了多个印迹簇中父本和母本甲基化印迹基因座的CpG dyad甲基化模式。我们确定与印记基因相关的父本和母本甲基化的次级差异甲基化区域均显示出高水平的半甲基化，为29–49％，而印记对照区域显示为8–12％的半甲基化。为了探索半甲基化的发生方式，我们评估了甲基化区域中是否存在5-羟甲基胞嘧啶，该甲基化可能通过被动和/或主动去甲基化机制导致甲基化丢失。我们在父本甲基化的次级甲基化差异区域中发现了5-羟甲基胞嘧啶的富集，但在本研究中分析的母本甲基化位点却未发现。我们发现高水平的半甲基化是与印迹基因相关的次级差异甲基化区域的普遍特征。我们建议5-羟甲基胞嘧啶富集可能负责与印记基因相关的父本甲基化的二级差异甲基化区域的甲基化状态的变化。我们进一步建议，必须通过在这些基因座处持续进行甲基化来抵消次级差异甲基化区域中半甲基化的高发生率。

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