Function of the human beta-globin locus control region

人β-珠蛋白基因座控制区的功能

• 批准号: 6541571
• 负责人: JORG BUNGERT
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541571
• 关键词: DNA binding protein; DNA directed RNA polymerase; DNA footprinting; artificial chromosomes; binding sites; cell cycle; chromatin; developmental genetics; erythroid stem cell; erythropoiesis; gene expression; gene mutation; genetic enhancer element; genetic promoter element; genetic transcription; genetically modified animals; globin; human genetic material tag; immunoprecipitation; intermolecular interaction; laboratory mouse; nucleoproteins; polymerase chain reaction; protein structure function; regulatory gene; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Many hemoglobinopathies are associated with mutations in the human Beta-globin gene locus and are characterized by diminished expression of one or several of the Beta-like globin genes. It is estimated that 3% of the world population carry mutations in the Beta globin locus and suffer from mild or severe anemia. The human Beta-globin genes are expressed in erythroid cells and are arranged in linear order on chromosome 11. The order of the genes reflects the timing of expression of individual globin genes during erythroid development. Recent work demonstrated that the locus control region (LCR), a powerful genetic DNA regulatory element located far upstream of the globin genes, is required for high-level globin gene expression throughout erythroid development. The LCR is composed of several regulatory modules that exhibit heightened sensitivity to various endo-nucleases. These sites are called hypersensitive (HS) sites and are binding sites for erythroid specific and ubiquitously expressed proteins. Although there is considerable debate as to how the LCR activates globin gene transcription, accumulating data suggest that in the human locus the individual HS sites cooperate to generate a higher order structure, referred to as the LCR holocomplex. The LCR holocomplex is thought to be generated by massive protein-DNA and protein-protein interactions that bring together the individual HS sites. In addition, recent data suggest that one of the functions attributable to the LCR is to serve as a primary attachment site for macromolecular complexes involved in chromatin remodeling and transcription. These macromolecular complexes are used to establish accessible chromatin domains and are subsequently transferred to individual globin gene promoters in a developmental stage specific manner. This proposal is aimed at addressing specific questions arising from this model. If correct, the model would explain locus control region function and would fundamentally contribute to understanding long-range regulation of chromatin structure and gene expression. It is expected that elucidating the mechanisms of globin gene regulation will benefit therapeutic attempts to treat hemoglobinopathies by introducing expression vectors mediating high-levels of wild-type Beta-globin gene expression into patients.

描述（由申请人提供）：许多血红蛋白病与人β-珠蛋白基因基因座中的突变有关，其特征是一种或几个类似β的球蛋白基因的表达降低。据估计，世界人口中有3％在β球蛋白基因座中携带突变，并且患有轻度或严重的贫血。人β-珠蛋白基因在红系细胞中表达，并在染色体11上以线性顺序排列。基因的顺序反映了红细胞发育过程中单个球蛋白基因表达的时间。最近的工作表明，位于球蛋白基因上游的强大遗传DNA调节元件（LCR）在整个红蛋白发育中都是高级球蛋白基因表达所必需的。 LCR由几个调节模块组成，这些模块对各种内核表现出更高的敏感性。这些位点称为超敏（HS）位点，是红细胞特异性和普遍表达蛋白的结合位点。尽管关于LCR如何激活球蛋白基因转录的争论存在很大的争论，但积累的数据表明，在人基因座中，单个HS位点配合以产生高阶结构，称为LCR全胶质体。 LCR全蛋白酶被认为是由大量蛋白-DNA和蛋白质 - 蛋白质相互作用产生的。此外，最近的数据表明，归因于LCR的功能之一是作为染色质重塑和转录涉及的大分子复合物的主要附件。这些大分子复合物用于建立可访问的染色质结构域，随后以发育阶段的特定方式转移至单个球蛋白基因启动子。该建议旨在解决该模型引起的特定问题。如果正确，该模型将解释基因座控制区域的功能，并从根本上有助于理解染色质结构和基因表达的长期调节。预计阐明球蛋白基因调节的机制将通过引入介导野生型β-蛋白基因表达的高水平的表达载体来使血红蛋白病的治疗尝试受益。