Loss of imprinting at the Dlk1-Gtl2 locus caused by insertional mutagenesis in the Gtl2 5' region.
Loss of imprinting at the Dlk1-Gtl2 locus caused by insertional mutagenesis in the Gtl2 5' region.
复制标题
由GTL2 5'区域中插入诱变引起的DLK1-GTL2基因座的印迹丧失。
DOI：
10.1186/1471-2156-7-44
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发表时间：
2006-10-03
期刊：
影响因子：
2.9
通讯作者：
Schmidt, Jennifer V.
中科院分区：
文献类型：
--
作者：
Steshina, Ekaterina Y.;Carr, Michael S.;Glick, Elena A.;Yevtodiyenko, Aleksey;Appelbe, Oliver K.;Schmidt, Jennifer V.
Dlk1 和 Gtl2 基因定义了小鼠 12 号染色体的一个区域，该区域受到基因组印记（基因的亲代等位基因特异性表达）的影响。尽管印记基因在生长和发育中发挥着重要作用，但人们对印记建立和维持的机制知之甚少。差异甲基化区域（DMR）仅在一个亲本等位基因上进行甲基化，参与许多位点的印记控制。 Dlk1-Gtl2 区域包含三个已知的 DMR，即 Dlk1 3' 区域中的 Dlk1 DMR、Gtl2 上游 15 kb 处的基因间 DMR 以及 Gtl2 启动子处的 Gtl2 DMR。这里分析了三种小鼠模型，提供了有关 Dlk1-Gtl2 印记调控的新信息。先前存在的插入突变 (Gtl2lacZ) 和其中 Gtl2 上游区域被 Neo 盒取代 (Gtl2Δ5'Neo) 的靶向缺失，在父系遗传时表现出部分致死性和侏儒症。分子表征表明，这两种突变都会导致 Dlk1、Gtl2 和 Meg8/Rian 基因印记丢失和表达变化。两种突变的父系遗传后，Dlk1 水平都会降低，这表明 Dlk1 可能是导致致死性和侏儒症的原因。 Gtl2lacZ 和 Gtl2Δ5'Neo 小鼠的父本染色体印记丢失都伴随着父本特异性 Gtl2 DMR 甲基化的丢失，而母本印记的丢失表明母本 Gtl2 DMR 具有以前未知的调节作用。出乎意料的是，当Neo基因被切除时，Gtl2Δ5'动物具有正常大小，印迹未改变并且Gtl2 DMR被正确甲基化。因此，整合到 Gtl2 上游的外源 DNA 序列负责生长和印记效应。这些数据为印记 Dlk1 和 Gtl2 基因的共调节提供了进一步的证据，并支持 Dlk1 作为重要的新生儿生长因子的作用。 Gtl2lacZ 和 Gtl2Δ5'Neo 突变能够引起印记和基因表达的远程变化，这表明区域印记调控元件可能位于整合位点附近。
The Dlk1 and Gtl2 genes define a region of mouse chromosome 12 that is subject to genomic imprinting, the parental allele-specific expression of a gene. Although imprinted genes play important roles in growth and development, the mechanisms by which imprinting is established and maintained are poorly understood. Differentially methylated regions (DMRs), which carry methylation on only one parental allele, are involved in imprinting control at many loci. The Dlk1-Gtl2 region contains three known DMRs, the Dlk1 DMR in the 3' region of Dlk1, the intergenic DMR 15 kb upstream of Gtl2, and the Gtl2 DMR at the Gtl2 promoter. Three mouse models are analyzed here that provide new information about the regulation of Dlk1-Gtl2 imprinting. A previously existing insertional mutation (Gtl2lacZ), and a targeted deletion in which the Gtl2 upstream region was replaced by a Neo cassette (Gtl2Δ5'Neo), display partial lethality and dwarfism upon paternal inheritance. Molecular characterization shows that both mutations cause loss of imprinting and changes in expression of the Dlk1, Gtl2 and Meg8/Rian genes. Dlk1 levels are decreased upon paternal inheritance of either mutation, suggesting Dlk1 may be causative for the lethality and dwarfism. Loss of imprinting on the paternal chromosome in both Gtl2lacZ and Gtl2Δ5'Neo mice is accompanied by the loss of paternal-specific Gtl2 DMR methylation, while maternal loss of imprinting suggests a previously unknown regulatory role for the maternal Gtl2 DMR. Unexpectedly, when the Neo gene is excised, Gtl2Δ5' animals are of normal size, imprinting is unchanged and the Gtl2 DMR is properly methylated. The exogenous DNA sequences integrated upstream of Gtl2 are therefore responsible for the growth and imprinting effects. These data provide further evidence for the coregulation of the imprinted Dlk1 and Gtl2 genes, and support a role for Dlk1 as an important neonatal growth factor. The ability of the Gtl2lacZ and Gtl2Δ5'Neo mutations to cause long-range changes in imprinting and gene expression suggest that regional imprinting regulatory elements may lie in proximity to the integration site.
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