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，对组蛋白修饰和转录因子结合模式的全基因组研究表明，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可变性，并且它们很可能代表了组织特异性的最重要决定因素

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.