红系分化中关键蛋白的精准调控是正常分化的前提，蛋白水平调控中去泛素化酶有重要功能，本课题前期数据显示去泛素化酶USP7在人红系分化终末阶段显著增加，已报道USP7可调控多种重要生命活动，但在红系分化中功能未知。我们发现敲低USP7延迟终末红系分化、抑制增殖及诱导凋亡；进一步发现USP7正调控红系核心转录因子GATA1蛋白表达水平并与其存在相互作用，且USP7在β-地中海贫血（β-TM）病人中表达下调。基于以上结果，我们提出如下科学假说：USP7是红系发育正常进行的必需分子，USP7去泛素化稳定GATA1维持红系发育正常进行；在β-TM患者中USP7下调引起GATA1下降导致红系分化阻滞和凋亡增加是无效造血的原因之一。本项目将在正常人与β-TM病人样本及小鼠中验证该科学假说，明确USP7在红系分化中的功能，丰富GATA1的调控机制，为治疗β-TM无效造血提供新靶标。

The precise regulation of key proteins in erythroid differentiation is essential for the maintenance of normal differentiation. The deubiquitination enzymes play an important roles in the regulation of protein levels. The preliminary data show that the ubiquitination enzyme USP7 increases during human terminal erythroid differentiation, the USP7 has been reported to regulate a variety of important biological processes, but its function in the erythropoiesis is unknown. Our preliminary data showed knock down of USP7 resulted in terminal erythroid differentiation delay, proliferation inhibition and apoptosis induction. Furthermore, we found that USP7 can positively regulate the key transcription factor GATA1 protein level and USP7 interacts with GATA1. In addition, we also found that compared with health donor, USP7 was decreased in β-thalassemia (β-TM) patients. Based on the preliminary results we propose the hypothesis that USP7 is essential for maintaining normal erythropoiesis through stabilizing GATA1; in β-TM, down-regulation of USP7 decreases GATA1 protein level, resulting in erythroid differentiation block and increased apoptosis, which is a possible cause of ineffective erythropoiesis. In this study, we will confirm the scientific hypothesis through some experiments carried out in normal case and β-TM patient samples and some mice, which will help clarify the functions of USP7 in erythroid differentiation and enrich the regulation mechanisms of GATA1 and provide new targets for ineffective erythropoiesis in β-TM.