MECHANISM AND FUNCTION OF GENOMIC IMPRINTING

描述(改编自调查员摘要)：少量 哺乳动物基因组中的基因由一个称为基因组的过程来调节。 印记，即母亲和父亲的等位基因是不同的 表达。这一过程需要配子特有的标记，很可能是DNA 印记基因附近特定序列的甲基化。这个 马克是从父母那里继承下来的，并在他们的后代中一直保持着 生活。基于人类和老鼠印记基因的突变，它是 很可能这一过程在哺乳动物中进化到调节产前和 可能是出生后早期发育。在人类对印记的破坏中 涉及三种遗传综合征，Beckwith-Wiedemann，Prader 威利和安杰曼综合征。此外，特定印记的丢失 已经在大量的人类肿瘤中观察到了基因。这 应用程序提出了了解人类肿瘤数量的实验。 这个应用程序建议进行实验，以了解 基因组印迹，以及这一过程的功能和进化。 实验室正在研究远端的一组印记基因。 包括四个母体表达的基因的小鼠7号染色体 编码生长因子胰岛素和胰岛素样生长因子II.A 提出了解释H19和Igf2相互印记的模型 这两个基因的启动子之间相距90kb，它们竞争的是 转录增强剂。尽管有大量证据表明 支持这一模式，为母体竞争奠定了基础 染色体还没有完全被理解。调查人员提议 产生H19基因的两个条件性突变，一个在启动子中 和第二个在5‘侧翼，以评估相对重要性 H19的转录与缺乏甲基化的要求 在其5‘侧翼的配子标记，用于印记Igf2的沉默。这个 配子标记的性质及其稳定DNA甲基化的获得 将通过转基因和转基因小鼠实验进行探索。 在雌性生殖系中防止其甲基化的蛋白质 并将在体细胞中进行鉴定和克隆。这一概念的普遍性 将通过研究端粒上的基因来探索竞争模型 群集的末尾。Gamtic印记将由以下人员识别和测试 转基因。探讨联动对印记的重要性 该区域中的基因，特定的易位将被改造成 使小鼠分离出这些基因的链接。最后，是关于 印记将在有袋类、单尾轮虫和两种 野鼠Permyscus的品系，在那里戏剧性的扰动 在正反交的F1中观察到了生长。

DESCRIPTION (Adapted from investigator's abstract): A small number of genes in the mammalian genome are regulated by a process called genomic imprinting, whereby the maternal and paternal alleles are differentially expressed. The process requires a gamete-specific mark, most likely DNA methylation of specific sequences in the vicinity of imprinted genes. The mark is inherited from parents, and maintained in their progeny throughout life. Based on mutations in both humans and mice in imprinted genes, it is likely that the process evolved in mammals to regulated prenatal and possibly early postnatal growth. In human disruptions in imprinting have been implicated in three genetic syndromes, Beckwith-Wiedemann, Prader Willi and Angelman syndromes. Furthermore, loss of imprinting of specific genes has been observed in a large number of human tumors. This application proposes experiments to understand the number of human tumors. This application proposes experiments to understand the mechanism of genomic imprinting, as well as the function and evolution of the process. The laboratory is studying a cluster of imprinted genes on the distal end of mouse Chromosome 7 that include four maternally expressed genes that encode the growth factors insulin and insulin-like growth factor II. A model was proposed to explain the reciprocal imprinting of H19 and Igf2 in which the promoters of the two genes, which lie 90 kb apart, compete for transcriptional enhancers. Although there is substantial evidence in support of this model, the basis for the competition on the maternal chromosome is not completely understood. The investigators propose to generate two conditional mutations of the H19 gene, one in the promoter and a second in the 5' flank, to assess the relative importance of transcription of H19 versus a requirement for lack of methylation of the gametic mark in its 5' flank, for the imprinted silencing of Igf2. The nature of the gametic mark, and its acquisition of stable DNA methylation will be explored using both transfections and transgenic mice experiments. The proteins that act to prevent its methylation in the female germline and in somatic cells will be identified and cloned. The generality of the competition model will be explored by studying the genes at the telomeric end of the cluster. Gametic imprints will be identified and tested by transgenesis. To explore the importance of linkage for the imprinting of the genes in the region, specific translocations will be engineered in mice to dissociate the linkage of the genes. Finally the evolution of imprinting will be studied in the marsupial, Monodelphis, and in two strains of the wild mouse Peromyscus, where dramatic perturbations in growth are observed in reciprocal F1 hybrids.