State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Japanese Red Cross Society, Department of Research and Development, Central Blood Institute, Tokyo, 105-8521, Japan.
Biochem Biophys Res Commun. 2021 May 7;552:157-163. doi: 10.1016/j.bbrc.2021.03.051. Epub 2021 Mar 19.
β-Thalassemia is an autosomal recessive genetic disease caused by defects in the production of adult hemoglobin (HbA, αβ), which leads to an imbalance between α- and non-α-globin chains. Reactivation of γ-globin expression is an effective strategy to treat β-thalassemia patients. Previously, it was demonstrated that hemoglobin subunit beta pseudogene 1 (HBBP1) is associated with elevated fetal hemoglobin (HbF, αγ) in β-thalassemia patients. However, the mechanism underlying HBBP1-mediated HbF production is unknown. In this study, using bioinformatics analysis, we found that HBBP1 is involved in γ-globin production, and then preliminarily confirmed this finding in K562 cells. When HBBP1 was overexpressed, γ-globin expression was increased at the transcript and protein levels in HUDEP-2 cells. Next, we found that ETS transcription factor ELK1 (ELK1) binds to the HBBP1 proximal promoter and significantly promotes its activity. Moreover, the synthesis of γ-globin was enhanced when ELK1 was overexpressed in HUDEP-2 cells. Surprisingly, ELK1 also directly bound to and activated the γ-globin proximal promoter. Furthermore, we found that HBBP1 and ELK1 can interact with each other in HUDEP-2 cells. Collectively, these findings suggest that HBBP1 can induce γ-globin by enhancing ELK1 expression, providing some clues for γ-globin reactivation in β-thalassemia.
β-地中海贫血是一种常染色体隐性遗传病，由成人血红蛋白（HbA，αβ）产生缺陷引起，导致α-和非α-珠蛋白链之间失衡。重新激活γ-珠蛋白的表达是治疗β-地中海贫血患者的有效策略。先前已经证明，血红蛋白亚单位β假基因 1（HBBP1）与β-地中海贫血患者的胎儿血红蛋白（HbF， αγ）升高有关。然而，HBBP1 介导的 HbF 产生的机制尚不清楚。在这项研究中，我们使用生物信息学分析发现 HBBP1 参与了 γ-珠蛋白的产生，然后在 K562 细胞中初步证实了这一发现。当 HBBP1 过表达时，HUDEP-2 细胞中 γ-珠蛋白的转录和蛋白水平均增加。接下来，我们发现 ETS 转录因子 ELK1（ELK1）与 HBBP1 近端启动子结合，并显著促进其活性。此外，当 ELK1 在 HUDEP-2 细胞中过表达时，γ-珠蛋白的合成增强。令人惊讶的是，ELK1 还可以直接结合并激活 γ-珠蛋白近端启动子。此外，我们发现 HBBP1 和 ELK1 可以在 HUDEP-2 细胞中相互作用。总之，这些发现表明 HBBP1 可以通过增强 ELK1 的表达来诱导 γ-珠蛋白，为β-地中海贫血中 γ-珠蛋白的重新激活提供了一些线索。
