MYC相关锌指蛋白调节HbF表达的分子机制及其对β地中海贫血表型修饰的研究

β地中海贫血(β地贫)是成人血红蛋白(HbA)缺陷导致的单基因致死性遗传病。胎儿血红蛋白(HbF)代偿性表达可缓解β地贫患者临床表型。但关于如何逆转HbA到HbF的血红蛋白开关这一关键问题有待深入研究。项目组前期利用CRISPR/Cas9敲除文库鉴定得到的MYC相关锌指蛋白(MAZ)对HbF表达有负调控功能。且ChIP-Seq数据分析表明MAZ蛋白可作用于ZBTB7A、KLF1基因启动子区和血红蛋白增强子LCR区，三者均可调控HbF表达。以此为基础，我们提出“MAZ通过调节已知HbF调控蛋白和LCR区参与血红蛋白开关转换”的假说。针对此假说，本项目拟选用β地贫造血干细胞和转基因动物为主要研究材料，采用基因干预和造血分化等技术，深入探讨MAZ通路调控HbF表达的分子机制，进而探索该通路对β地贫的表型修饰作用。研究结果可扩充血红蛋白转换机制的新知识，为寻找β地贫治疗药物提供新的思路与实验线索。

β-thalassemia is a monogenic lethal genetic disease resulting from the deficiency of adult hemoglobin (HbA). The compensatory expression of fetal hemoglobin (HbF) may ameliorate the clinical severity of β-thalassemia patients. However, the key question about how to reverse the HbA to HbF switch needs further study. The MYC associated zinc finger protein (MAZ) identified by the CRISPR / Cas9 knockout library in the early stage of the project team has negative regulatory functions on HbF expression. Moreover, ChIP-Seq data analysis showed that MAZ protein can bind to the gene promoter of ZBTB7A and KLF1, and Locus control region (LCR), all of which can regulate HbF expression. In this proposal, our central hypothesis is that MAZ participates in hemoglobin switch by regulating known HbF regulatory proteins and the LCR. To test this hypothesis, we will use transgenic animals, mediterranean anemia derived hematopoietic stem cells (HSCs) as the main research materials to identify the role of MAZ in HbF regulation by gene intervention and hematopoietic differentiation. We will explore the phenotypic modification of β-thalassemia by the MAZ pathway. The completion of these exciting studies will not only provide new perspectives on the mechanism of hemoglobin switch, but also identify a potential strategy for β-thalassemia therapy.