TEA domain transcription factor 4 modulates repression of fetal haemoglobin by direct binding to the γ‐globin gene promoters
TEA domain transcription factor 4 modulates repression of fetal haemoglobin by direct binding to the γ‐globin gene promoters
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TEA 结构域转录因子 4 通过直接结合γ珠蛋白基因启动子来调节胎儿血红蛋白的抑制
DOI：
10.1111/bjh.17786
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发表时间：
2021
影响因子：
6.5
通讯作者：
Xiangmin Xu
中科院分区：
文献类型：
--
作者：
Jiaqiong Lin;Yuhua Ye;Xuan Shang;Yanxia Zhang;Xiaofeng Wei;Xiangmin Xu
胎儿血红蛋白（HbF）的重新激活已被证明是治疗β-血红蛋白病的有效策略。在这项研究中，我们通过将公共数据集与β地中海贫血患者的定量聚合酶链反应分析相结合，确定 TEA 域转录因子 4 (TEAD4) 是 HbF 的新潜在调节剂。 β地中海贫血患者TEAD4表达与HbF水平呈显着负相关。 β-地中海贫血 CD34+ 细胞和 HUDEP-2 细胞中 TEAD4 抑制的功能验证表明，TEAD4 的消耗导致 HbF 显着增加。最后，我们在γ-球蛋白基因启动子上鉴定了TEAD4的结合基序；它的破坏始终导致 HbF 的抑制解除。综上所述，这些结果表明 TEAD4 可以通过直接结合到 γ-珠蛋白基因的启动子上作为 γ-珠蛋白基因的转录抑制剂。我们的研究结果证明了 TEAD4 在 HbF 调节中的新作用，这可能有益于 β-血红蛋白病患者。
Re‐activation of fetal haemoglobin (HbF) has been proved to be an effective strategy for the treatment of β‐haemoglobinopathies. In this study, we identified TEA domain transcription factor 4 (TEAD4) as a new potential regulator of HbF by integrating public data sets with quantitative polymerase chain reaction analysis in β‐thalassaemia patients. Significant negative correlation was observed between the expression ofTEAD4and HbF levels in β‐thalassaemia patients. Functional validations ofTEAD4inhibition in both β‐thalassaemia CD34+cells and HUDEP‐2 cells indicated that depletion ofTEAD4led to a significant increase of HbF. Finally, we identified a binding motif ofTEAD4on γ‐globin gene promoters; its disruption consistently led to de‐repression of HbF. Taken together, these results demonstrate thatTEAD4could act as a transcriptional inhibitor of the γ‐globin gene through direct binding on its promoter. Our findings demonstrate a novel role ofTEAD4on the regulation of HbF, which may benefit patients with β‐haemoglobinopathies.