MECHANISMS OF GENOMIC IMPRINTING

最近的实验表明，关于母本和父本基因组贡献相等的旧假设是不正确的，而且对于重要的基因，通常只有一个亲本等位基因得到表达。这种现象被称为基因组印记，因为据推测，父母的一个等位基因已经被生化印记标记了。印记可能解释了这样一个事实，即如果基因是从父亲那里继承的，那么一些遗传病可能会比从母亲那里继承的更容易发生，反之亦然。印记不仅是正常发育所必需的，而且某些基因印记过程的失败可能会导致肿瘤发生的倾向。印迹基因经常参与细胞生长的调节。因此，印迹过程中的变化很可能导致异常生长和发育。印迹是一种塑料现象，表现出启动子、组织和发育的特殊性。这笔赠款的具体目的如下：1.我们的目标是了解在正常组织和发育过程中连续的胰岛素样生长因子-II(IGF2)和H19基因相互协调印记的机制。为此，我们基于我们在Igf2上游发现的一个假定的印记维持元件开发了一个模型，该元件同时调节Igf2和H19印记。我们计划使用体外和体内转基因系统来测试这个模型。2.为了了解印记过程的可塑性，我们选择了研究Igf2，一个以启动子特异性、组织特异性和发育特异性的方式印记的基因。我们将比较Igf2在中枢神经系统中的表达，这是一个从所有四个启动子中以双等位方式唯一表达Igf2的组织，以及它在其他组织中的表达，在其他组织中总是印记着它。特别是，我们将研究DNA甲基化、组蛋白乙酰化和反义如何调节这个印记基因的表达。

Recent experiments have shown that old assumptions about the equal contributions of the maternal and paternal genomes are incorrect and that for important genes, only one of the parental alleles is normally expressed. This phenomenon is called genomic imprinting because one of the parental alleles has presumably been marked by a biochemical imprint. Imprinting may account for the fact that some genetic diseases may occur more often if the gene is inherited from the father than from the mother or vice versa. Not only is imprinting required for normal development, but the failure of the imprinting process for some genes may lead to a proclivity for oncogenesis. Imprinted genes are frequently involved in the regulation of cell growth. Thus, it is likely that alterations in the imprinting process may lead to aberrant growth and development. Imprinting is a plastic phenomenon which demonstrates promoter, tissue, and developmental specificities. The Specific Aims of this grant are as follows: 1. Our goal is to understand the mechanisms underlying the coordinate yet reciprocal imprinting of the contiguous insulin-like growth factor-II (Igf2) and H19 genes in normal tissues and during development. To this end, we have developed a model based on our discovery of a putative imprinting maintenance element upstream of Igf2 which regulates both Igf2 and H19 imprinting. We plan to test this model using in vitro as well as in vivo transgenic systems. 2. To understand the plasticity of the imprinting process, we have chosen to study Igf2, a gene which is imprinted in a promoter-specific, tissue-specific, and development-specific manner. We will compare Igf2 expression in the central nervous system, a tissue which uniquely expresses Igf2 biallelically from all four promoters, with its expression from other tissues in which it is always imprinted. In particular, we will examine how DNA methylation, histone acetylation and antisense regulate the expression of this imprinted gene.