Enhancers and hyperacetylated domains in erythropoiesis

描述(由申请人提供)：正常的细胞分化过程涉及组织特异性基因表达的协调程序。最近，全基因组范围的组蛋白修饰和转录因子结合模式的方法揭示了启动子-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的最重要的决定因素。 基因表达。以红系分化为模型系统，我们已经研究了高乙酰化结构域的现象，它由广泛分布的(&gt；12kb)组蛋白修饰模式组成，通常仅限于活性基因的启动子-近端区域，我们积累的证据表明，这种结构域代表了一类特定的远端增强子元件的功能。因此，我们有兴趣研究这些增强子介导结构域形成的机制，以便深入了解高乙酰化结构域如何在末端分化过程中促进组织特异性基因的激活。为此，我们将详细研究候选的红系特异性结构域形成增强剂，以确定它们活性所需的DNA结合因子， 进而产生相关的辅因子和组蛋白修饰酶。此外，我们将定义在红系和肝细胞中活跃的基因位点上形成结构域的要求，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在红系成熟过程中介导红系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.