Human Globin Gene Regulation During Development

描述（由申请人提供）：人类从胎儿血红蛋白到成人血红蛋白的转换受转录因子调节，这些转录因子增强或抑制γ-或β-珠蛋白基因与强大的基因座控制区的相互作用。我们最近证明，敲低人类和小鼠成年红系祖细胞中的KLF 1可降低BCL 11 A水平，并增加人类γ-珠蛋白与β-珠蛋白基因表达比率。这些结果表明KLF 1通过直接激活β-珠蛋白和间接抑制γ-珠蛋白基因表达来控制珠蛋白基因转换。此外，我们最近分离出一种蛋白质（FOKLF 1; KLF 1的朋友），它与KLF 1复合并激活β-珠蛋白基因表达。有趣的是，FOKLF 1的敲除显著增加了人类γ-珠蛋白与β-珠蛋白基因的比例。这些结果表明，在成人红系祖细胞中FOKLF 1的受控敲除或药理学抑制可以提供一种用于激活β地中海贫血和镰状细胞病患者的胎儿血红蛋白的方法。本研究的具体目的如下：（1）确定FOKLF 1基因的结构域;（2）确定FOKLF 1基因和KLF 1基因的调控元件。(3)识别FOKLF 1基因突变/变异的HPFH（胎儿血红蛋白遗传性持续性）个体。

DESCRIPTION (provided by applicant): The switch from fetal to adult hemoglobin in humans is regulated by transcription factors that enhance or inhibit interactions of the gamma- or beta-globin gene with the powerful Locus Control Region. We recently demonstrated that knockdowns of KLF1 in human and mouse adult erythroid progenitors reduce BCL11A levels and increase human gamma- to beta-globin gene expression ratios. These results suggest that KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. In addition, we have recently isolated a protein (FOKLF1; Friend of KLF1) that complexes with KLF1 and activates beta-globin gene expression. Interestingly, knockdowns of FOKLF1 dramatically increase human gamma- to beta-globin gene ratios. These results suggest that controlled knockdown or pharmacological inhibition of FOKLF1 in adult erythroid progenitors may provide a method for activating fetal hemoglobin in patients with beta-thalassemia and sickle cell disease. The Specific Aims of our proposal are as follows: (1) To define FOKLF1 domains essential for gamma- to beta-globin genes witching (2) To define FOKLF1 and KLF1 gene regulatory elements responsible for the up-regulation of these genes during development. (3) To identify HPFH (Hereditary Persistence of Fetal Hemoglobin) individuals who have mutations/variations in the FOKLF1 gene.