γ-珠蛋白基因表达调控机制与临床应用

Regulation of γ-globin gene expression and its clinical applications

成人体内的血红蛋白是由2个α-珠蛋白和2个β-珠蛋白组成的四聚体,负责氧气的运输。珠蛋白基因在基因组中成簇分布,其表达受到多种顺式作用元件和反式作用因子的共同调控,具有高度的组织特异性和发育时序性。β-地中海贫血和镰刀型细胞贫血是两种最常见的由于β-珠蛋白基因突变引起的常染色体隐性遗传病。γ-珠蛋白是一种主要在胎儿时期表达的类β-珠蛋白,同样具有载氧功能,但编码该蛋白的基因在上述贫血患者中却保持完好。因此,临床上优选的治疗方案之一是重新激活患者体内沉默的γ-珠蛋白基因的表达来弥补缺损的β-珠蛋白,从而缓解临床症状。目前已有多种能提高γ-珠蛋白基因表达的药物,在临床上用于治疗β-地中海贫血和镰刀型细胞贫血。随着基因组编辑技术的发展,针对这两种贫血的精准基因治疗研究也在进行中。本文着重介绍了参与γ-珠蛋白基因调控的转录因子和表观遗传修饰分子,以及目前相关的β-地中海贫血和镰刀型细胞贫血的临床治疗药物和手段,以期为深入阐明γ-珠蛋白基因的转录表达分子调控机制提供参考。

Human hemoglobin, a tetramer containing two α globins and two β globins, is responsible for oxygen transportation in the body. Globin genes are clustered in the genome and their expressions are regulated by a variety of cis-acting elements and trans-acting factors, exhibiting a developmental-and tissue-specific manner. b-thalassemia and sickle cell diseases are two of the most common autosomal recessive disorders caused by mutations in the b-globin gene. Besides a-and β-globins, the human genome also has a third globin gene—γ-globin. Like b-globin, γ-globin also has oxygen-carrying capabilities. Unlike β-globin, γ-globin is mainly expressed at the fetal stage and remains intact in b-thalassemia and sickle cell disease patients. Thus, reactivating the expression of the γ-globin gene in adult patients to ameliorate their clinical symptoms has become one of the best therapeutic strategies to treat β-thalassemia and sickle cell diseases. Some drugs have been developed clinically to increase γ-globin gene expression for those patients. With the development of genome editing technologies, precision gene therapy for these diseases is underway. This review focuses on the main transcription factors and epigenetic modifiers that are involved in γ-globin gene regulation, and some applications for clinical treatment for β-thalassemia and sickle cell diseases based on these studies. We hope to provide a useful reference for in-depth studies on transcriptional regulation of γ-globin gene expression in the future.