3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression.
3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression.
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DOI：
10.7554/elife.70557
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发表时间：
2021-09-29
期刊：
影响因子：
7.7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Himadewi P;Wang XQD;Feng F;Gore H;Liu Y;Yu L;Kurita R;Nakamura Y;Pfeifer GP;Liu J;Zhang X
成人β-珠蛋白基因的突变可能会导致多种血红蛋白疾病，包括镰状细胞病和β-地中海贫血。在成年期增加胎儿血红蛋白的表达，这是一种称为遗传性胎儿血红蛋白持续性(HPFH)的疾病，已被发现可以改善血红蛋白疾病。去除性hpfh是通过切除β-珠蛋白基因3‘端的一大部分，包括称为3’hs1的ctcf结合位点而发生的。在这里，我们表明，仅此CTCF位点的缺失就可以诱导成人CD34+造血干/祖细胞和HUDEP-2红系祖细胞中胎儿血红蛋白的表达。这种诱导是由位于该基因座下游的OR52A1基因下游的一个先前假设的远端增强子的异位访问驱动的，该增强子也可以通过3‘HS1 CTCF位点的倒置来隔离。这表明，对该结合位点的基因编辑可能对治疗血红蛋白疾病具有治疗意义。
Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named hereditary persistence of fetal hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3′ end of the β-globin locus, including a CTCF binding site termed 3′HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3′HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies.