Enhancers and hyperacetylated domains in erythropoiesis

红细胞生成中的增强子和超乙酰化结构域

基本信息

批准号：
8680225
负责人：
MICHAEL D BULGER
金额：
$ 23.03万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680225
关键词：
Address Adult Affinity Binding Biochemical Biological Assay Biological Models Cell physiology Chromatin Chromatin Structure Complex DNA Binding DNA Sequence Development Disease Distal Distal Enhancer Elements Elements Embryo Enhancers Enzymes Episome Erythrocytes Erythroid Erythroid Cells Erythropoiesis Exhibits Gene Activation Gene Expression Gene Expression Profile Gene Expression Regulation Genes Globin Goals Grant Hepatocyte Histones Lead Liver Mammalian Cell Maps Mediating Modeling Mutation Pattern Process Production Recruitment Activity Regulatory Element Reporter Genes Sampling Somatropin Staging Tissue-Specific Gene Expression Tissues Transgenes base cell type cofactor comparative erythroid differentiation genetic manipulation genome-wide histone modification in vivo insight interest member novel programs promoter public health relevance transcription factor

项目摘要

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.

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变异性，并且它们很可能代表组织特异性的最重要的决定因素。基因表达。使用红系分化作为模型系统，我们之前研究了超乙酰化结构域的现象，该结构域由广泛分布的（> 12 kb）组蛋白修饰模式组成，通常仅局限于活性基因的启动子近端区域，并且我们已经积累了证据表明这些结构域代表了特定类别的远端增强子元件的功能。因此，我们有兴趣研究此类增强子介导结构域形成的机制，以便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红细胞特异性结构域形成增强剂，以确定其活性所需的 DNA 结合因子，以及相关的辅因子和组蛋白修饰酶。此外，我们将定义在红细胞和肝细胞中活跃的基因位点形成结构域的要求，从而确定不同细胞类型中结构域之间的共同特征。从这些研究中，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。