Enhancers and hyperacetylated domains in erythropoiesis

描述（由申请人提供）：细胞分化的正常过程涉及组织特异性基因表达的协调程序。最近，绘制组蛋白修饰和转录因子结合模式的全基因组方法已经揭示，启动子远端增强子序列在不同的哺乳动物细胞类型中表现出最大的变异性，并且它们最有可能代表组织特异性转录因子的最重要决定因素。 基因表达。使用红细胞分化作为一个模型系统，我们以前已经研究了超乙酰化结构域的现象，其中包括广泛分布（> 12 kb）的组蛋白修饰模式，通常仅限于启动子近端区域的活性基因，我们已经积累的证据表明，这样的结构域代表了一个特定类别的远端增强子元件的功能。因此，我们有兴趣研究这种增强子介导结构域形成的机制，以深入了解超乙酰化结构域如何在终末分化过程中促进组织特异性基因激活。为此，我们将详细研究候选的红细胞特异性结构域形成增强子，以鉴定其活性所需的DNA结合因子， 并依次与相关的辅因子和组蛋白修饰酶结合。此外，我们将定义在红细胞和肝细胞中活性基因位点的结构域形成的要求，从而确定不同细胞类型中结构域之间的共同特征。通过这些研究，我们希望阐明远端增强子介导红系细胞成熟过程中红系细胞特异性基因激活的具体机制。

DESCRIPTION (provided by applicant): Normal processes of cellular differentiation involve coordinated programs of tissue-specific gene expression. Recently, genome-wide approaches to mapping histone modification and transcription factor binding patterns have revealed that promoter-distal enhancer sequences exhibit the greatest variability among distinct mammalian cell types, and that they most likely represent the most significant determinant of tissue-specific gene expression. Using erythroid differentiation as a model system, we have previously investigated the phenomenon of hyperacetylated domains, which consist of broadly-distributed (>12 kb) patterns of histone modifications that are usually confined solely to the promoter-proximal regions of active genes, and we have accumulated evidence that such domains represent a function of a specific class of distal enhancer element. We are therefore interested in investigating the mechanism by which such enhancers mediate domain formation, in order to gain insight into how hyperacetylated domains contribute to tissue-specific gene activation during terminal differentiation. To do this, we will investigate candidate erythroid-specific domain-forming enhancers in detail to identify the DNA-binding factors required for their activity, and in turn the associated cofactors and histone modifying enzymes. In addition, we will define the requirements for domain formation at a gene locus active in both erythroid and liver cells, and thus determine the features common between domains in different cell types. From these studies, we hope to elucidate the specific mechanisms by which distal enhancers mediate erythroid-specific gene activation during erythroid maturation.