Paoloni-Giacobino Ariane, D'Aiuto Leonardo, Cirio M Cecilia, Reinhart Bonnie, Chaillet J Richard
Department of Molecular Genetics and Biochemistry University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Gene. 2007 Sep 1;399(1):33-45. doi: 10.1016/j.gene.2007.04.028. Epub 2007 May 1.
Genomic imprinting is a conserved epigenetic phenomenon in eutherian mammals, with regards both to the genes that are imprinted and the mechanism underlying the expression of just one of the parental alleles. Epigenetic modifications of alleles of imprinted genes are established during oogenesis and spermatogenesis, and these modifications are then inherited. Differentially methylated domains (DMDs) of imprinted genes are the genomic sites of these inherited epigenetic imprints. We previously showed that CpG-rich imperfect tandem direct repeats within three different mouse DMDs (Snurf/Snrpn, Kcnq1 and Igf2r), each with a unique sequence, play a central role in maintaining the differential methylation. This finding implicates repeat-related DNA structure, not sequence, in the imprinting mechanism. To better define the important features of this signal, we compared sequences of these three DMD tandem repeats among mammalian species. All DMD repeats contain short indirect repeats, many of which are organized into larger unit repeats. Even though the larger repeat units undergo deletion and addition during evolution (most likely through unequal crossovers during meiosis), the size of DMD tandem repeated regions has remained remarkably stable during mammalian evolution. Moreover, all three DMD tandem repeats have a high-CpG content, an ordered arrangement of CpG dinucleotides, and similar predicted secondary structures. These observations suggest that a structural feature or features of these DMD tandem repeats is the conserved DMD imprinting signal.
基因组印记是真兽亚纲哺乳动物中一种保守的表观遗传现象，涉及被印记的基因以及仅一个亲本等位基因表达背后的机制。印记基因等位基因的表观遗传修饰在卵子发生和精子发生过程中建立，然后这些修饰被遗传。印记基因的差异甲基化区域（DMDs）是这些遗传表观遗传印记的基因组位点。我们之前表明，三种不同小鼠DMD（Snurf/Snrpn、Kcnq1和Igf2r）内富含CpG的不完全串联直接重复序列，每个都有独特的序列，在维持差异甲基化中起核心作用。这一发现表明，印记机制中涉及的是与重复相关的DNA结构而非序列。为了更好地定义这种信号的重要特征，我们比较了哺乳动物物种中这三种DMD串联重复序列的序列。所有DMD重复序列都包含短的间接重复序列，其中许多被组织成更大的单位重复序列。尽管较大的重复单位在进化过程中经历了缺失和添加（很可能是通过减数分裂期间的不等交换），但DMD串联重复区域的大小在哺乳动物进化过程中保持了显著的稳定性。此外，所有三种DMD串联重复序列都具有高CpG含量、CpG二核苷酸的有序排列以及相似的预测二级结构。这些观察结果表明，这些DMD串联重复序列的一种或多种结构特征是保守的DMD印记信号。
