MAPPING OF CHROMATIN BORDER ELEMENTS IN THE MAMMALIAN GENOME

哺乳动物的染色体是由一系列超卷曲的环状 结构域长度约为100个酶，每个酶的末端连接着一个 核基质这些环或染色质结构域是功能单位 每个独立的结构域都可以 以活性染色质或非活性染色质的形式组装。我们长久以来- 术语的目的是了解染色质结构域的功能， 组成它们的元素，这样我们就可以获得一个完整的 了解基因表达的调节以及它如何 用于基础研究、医学（基因和癌症治疗）和 商业（药物生产和递送）应用。 大多数研究都集中在附近的调控因素 基因，包括启动子和增强子元件，蛋白质结合到 这些，以及启动子周围的DNA修饰。如今， 很明显，关键的控制因素往往多达几百个 从一个结构确定的单位内的基因，我们有 称为染色质结构域。很少有这样的功能域已经被 在任何细节的特点，当他们有办法一般有 通常是寻找一种或几种类型的调节元件。 要彻底理解，我们需要在 细节，使用一系列方法来识别所有潜在的 这些领域的重要调控因素。虽然矩阵 附着区、复制起点和绝缘子，能够 抑制一个结构域中的启动子和增强子之间的相互作用 在另一种情况下，在某些情况下可能共同出现，这些元素仍然可以 功能上不同，不一定重叠。只有通过 在一些我们希望能 这些重要的区别。域的详细映射将允许 我们确定这些领域的关键监管要素， 为将来的研究做准备，我们计划在未来的研究中测试这些元素， 实验系统，或删除或改变它们。初始映射我们 这里提出的建议不仅可以让我们理解和操纵这些 特定领域更好，但希望能揭示一般特征， 也将加速我们绘制其他领域地图的能力。

Mammalian chromosomes are organized as a series of supercoilable looped domains about 100 kilobases in length, each tethered at its end to a nuclear matrix. These loops or chromatin domains are the functional units of transcriptional competence in that each independent domain can be assembled either as active chromatin or as inactive chromatin. Our long- term objective is to understand the function of chromatin domains and the elements that comprise them so that we may acquire a complete understanding of the regulation of gene expression and how it may be manipulated for basic research, medical (gene and cancer therapy) and commercial (drug production and delivery) applications. Most studies have focused on regulatory elements in the immediate vicinity of genes, including promoter and enhancer elements, proteins binding to these, and DNA modification around the promoter. It is now abundantly clear that crucial control elements often lie as much as several hundred kilobases from a gene within a structurally-defined unit which we have referred to as the chromatin domain. Few such functional domains have been characterized in any detail, and when they have the approach has generally has generally been a search for one or a few types of regulatory elements. A thorough understanding requires that we map a number of domains in detail, using a battery of methods to identify all of the potentially important regulatory elements in those domains. Although a matrix attachment region, a replication origin and an insulator, capable of dampening the interaction between a promoter in one domain and an enhancer in another, could co-occur in some instances, these elements may still be functionally distinct and not necessarily overlapping. It is only by mapping out all such elements in a number of cases that we expect to make these important distinctions. The detailed mapping of domains will allow us to identify the crucial regulatory elements in those domains, in preparation for future studies in which we plan to test these elements in experimental systems, or to delete or alter them. The initial mapping we propose here will not only allow us to understand and manipulate these particular domains better, but will hopefully reveal general features that will accelerate our ability to map other domains as well.