REGULATION OF HUMAN GAMMA GLOBIN GENE

人类血红蛋白的产生在发育过程中由 定位的两个多基因家族的协同和顺序表达 在11号和16号染色体上。胎儿和成人之间的血红蛋白转换 产生的结果是成对的伽马珠蛋白基因失活 以及β珠蛋白基因的激活。此开关在 被称为遗传性胎儿血红蛋白持续存在的情况的数量 (HPFH)。一类HPFH变异体是由于 伽玛珠蛋白基因启动子和上游序列。我们最后一次的工作 授权期一直侧重于确定高额 单碱基改变引起的伽马珠蛋白基因表达 G-γ珠蛋白基因的-202位。我们的研究表明， 一个无处不在的因素束缚在这个位置，并可能起到抑制作用 伽马珠蛋白基因的表达。在目前的提案中，我们计划 进一步描述这一因素，确定其在影响 丙种球蛋白基因转录复合体的组装 启动子，并确定可能的相互作用的伽马珠蛋白基因 与珠蛋白基因结构域中的其他元件的转录复合体， 尤其是3‘-γ珠蛋白基因增强子及其基因座控制 地区。这些研究旨在确定生物化学 调节伽马珠蛋白基因表达的机制，并开发新的 可能导致成人伽马珠蛋白基因修饰的概念。

Human hemoglobin production is regulated during development by the coordinate and sequential expression of two multigene families located on chromosomes 11 and 16. The switch between fetal and adult hemoglobin production results from the inactivation of the paired gamma globin genes and activation of the beta globin gene. This switch is impaired in a number of conditions termed hereditary persistence of fetal hemoglobin (HPFH). One class of HPFH variants are due to single base changes in the gamma globin gene promoters and upstream sequences. Our work in the last granting period has been focused on determining the mechanism for high gamma globin gene expression resulting from single base changes at position -202 of the G gamma globin gene. Our studies have revealed that a ubiquitous factor binds at this position and possibly serves to repress gamma globin gene expression. In the current proposal, we plan to further characterize this factor, determine its role in affecting the assembly of the transcriptional complex of the gamma globin gene promoter, and determine the possible interaction f the gamma globin gene transcriptional complex with other elements in the globin gene domain, especially the 3' gamma globin gene enhancer and the Locus Control Region. These studies are intended to determine the biochemical mechanisms that regulate gamma globin gene expression, and to develop new concepts that may lead to a modification of gamma globin genes in adults.