Function of the human beta-globin locus control region

描述（由申请人提供）：许多血红蛋白病与人β-珠蛋白基因座突变相关，特征为一种或几种β-样珠蛋白基因表达减少。据估计，3%的世界人口携带β珠蛋白基因座突变，并患有轻度或重度贫血。人β-珠蛋白基因在红系细胞中表达，并在11号染色体上以线性顺序排列。基因的顺序反映了红系发育过程中单个珠蛋白基因表达的时间。最近的工作表明，基因座控制区（LCR），一个强大的遗传DNA调控元件位于珠蛋白基因的上游，是需要高水平的珠蛋白基因表达在整个红系发育。LCR由几个调节模块组成，这些模块对各种内切核酸酶表现出高度的敏感性。这些位点被称为超敏（HS）位点，是红细胞特异性和普遍表达的蛋白质的结合位点。尽管LCR如何激活珠蛋白基因转录存在相当大的争议，但积累的数据表明，在人类基因座中，各个HS位点合作产生更高级的结构，称为LCR全复合物。LCR全复合物被认为是由大量的蛋白质-DNA和蛋白质-蛋白质相互作用产生的，这些相互作用将各个HS位点聚集在一起。此外，最近的数据表明，归因于LCR的功能之一是作为参与染色质重塑和转录的大分子复合物的主要附着位点。这些大分子复合物用于建立可接近的染色质结构域，并随后以发育阶段特异性方式转移到单个珠蛋白基因启动子。这项建议旨在解决这一模式产生的具体问题。如果正确的话，该模型将解释基因座控制区的功能，并将从根本上有助于理解染色质结构和基因表达的长期调控。预期阐明珠蛋白基因调控的机制将有益于通过将介导高水平野生型β-珠蛋白基因表达的表达载体引入患者来治疗血红蛋白病的治疗尝试。

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.