Increased plasticity of genomic imprinting of Dlk1 in brain is due to genetic and epigenetic factors
Increased plasticity of genomic imprinting of Dlk1 in brain is due to genetic and epigenetic factors
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DOI：
10.1007/s00335-004-2434-9
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发表时间：
2005-02-01
期刊：
影响因子：
2.5
通讯作者：
Naumova, AK
中科院分区：
文献类型：
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作者：
Croteau, S;Roquis, D;Naumova, AK
在源自 C57BL/6 和 MOLF/Ei 品系 N-2 x N-2 杂交的 21 只小鼠的大脑中检查了 6 个印记基因（Dlk1、Gtl2、Igf2r、Kcnq1、Nnat 和 Peg1）的表达。 Igf2r、Kcnq1、Gtl2 和 Dlk1 的印记因人而异。由于其中三个基因涉及细胞-细胞信号传导或细胞-环境相互作用，因此它们印记的变化可能会影响从细胞分化到行为的广泛生物过程。为了阐明大脑个体间印记变异的机制，我们将注意力集中在父系表达的基因 Dlk1 上。我们研究了 N-9 和 N-10 回交动物大脑中 Dlk1 的表达，发现 N-9 和 N-10 小鼠中通常沉默的母体 Dlk1 等位基因的重新激活发生率低于 N2 x N2 动物。我们的数据表明，MOLF/Ei 起源的反式作用遗传因子促进了通常沉默的母体 Dlk1 等位基因的重新激活。我们将这些因素之一映射到 Chr 7 的近端部分。亚硫酸氢盐测序甲基化分析的结果表明，母体等位基因的重新激活也与基因内差异甲基化区域 (IG DMR) 的高甲基化相关，该区域是 Dlk1-Gtl2 结构域的印记控制区域。因此，Dlk1 在大脑中的印记状态取决于反式遗传影响，并与 IG DMR 特定亚区的甲基化状态相关。
The expression of six imprinted genes (Dlk1, Gtl2, Igf2r, Kcnq1, Nnat, and Peg1) was examined in brains of 21 mice derived from N-2 x N-2 intercrosses between C57BL/6 and MOLF/Ei strains. Imprinting of Igf2r, Kcnq1, Gtl2, and Dlk1 varied among individuals. As three of these genes are implicated in cell-cell signaling or cell-environment interactions, variation in their imprinting may influence a wide range of biological processes from cell differentiation to behavior. To elucidate the mechanisms underlying the interindividual imprinting variation in the brain, we focused our effort on the paternally expressed gene Dlk1. We investigated expression of Dlk1 in the brains of animals from N-9 and N-10 backcrosses and found that reactivation of the normally silent maternal Dlk1 allele in the N-9 and N-10 mice occurred less often than in N2 x N2 animals. Our data suggest that trans-acting genetic factors of MOLF/Ei origin facilitate the reactivation of the normally silent maternal allele of Dlk1. We mapped one of these factors to the proximal part of Chr 7. The results of bisulfite sequencing methylation analysis show that reactivation of the maternal allele was also associated with hypermethylation of the intragenic differentially methylated region (IG DMR), which is the imprinting control region for the Dlk1-Gtl2 domain. Thus, the imprinting status of Dlk1 in the brain depends upon trans-acting genetic influences and correlates with the methylation status of a specific subregion of the IG DMR.