Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and β-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-to-adult developmental transition. To explore the effects of LIN28B in human erythroid cell development, lentiviral transduction was used to knockdown LIN28B expression in erythroblasts cultured from human umbilical cord CD34+ cells. The subsequent reduction in LIN28B expression caused increased expression of let-7 and significantly reduced HbF expression. Conversely, LIN28B overexpression in cultured adult erythroblasts reduced the expression of let-7 and significantly increased HbF expression. Cellular maturation was maintained including enucleation. LIN28B expression in adult erythroblasts increased the expression of γ-globin, and the HbF content of the cells rose to levels >30% of their hemoglobin. Expression of carbonic anhydrase I, glucosaminyl (N-acetyl) transferase 2, and miR-96 (three additional genes marking the transition from fetal-to-adult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of γ-globin expression, was significantly down-regulated. Independent of LIN28B, experimental suppression of let-7 also reduced BCL11A expression and significantly increased HbF expression. LIN28B expression regulates HbF levels and causes adult human erythroblasts to differentiate with a more fetal-like phenotype.

译文

:胎儿血红蛋白(HbF)的重新激活对镰状细胞病和β地中海贫血具有治疗潜力。在人类红系细胞和造血器官中,LIN28B及其靶向的let-7 microRNA家族在胎儿到成人的发育过渡过程中表现出调控的表达。为了探索LIN28B在人类红系细胞发育中的作用,慢病毒转导被用于敲除从人脐带CD34细胞培养的成红细胞中LIN28B的表达。 LIN28B表达的随后降低导致let-7表达增加,并且HbF表达显着降低。相反,在培养的成年成红细胞中LIN28B的过表达降低let-7的表达并显着增加HbF的表达。维持细胞成熟,包括去核。成年成红细胞中LIN28B的表达增加了γ-珠蛋白的表达,并且细胞中的HbF含量上升至血红蛋白的> 30%。 LIN28B的表达降低了碳酸酐酶I,氨基葡萄糖(N-乙酰基)转移酶2和miR-96(其他三个标记从胎儿到成人的红细胞生成的基因)的表达。转录因子BCL11A,一个公认的γ-珠蛋白表达阻遏物,被显着下调。独立于LIN28B,let-7的实验抑制作用还降低了BCL11A表达,并显着提高了HbF表达。 LIN28B表达调节HbF水平,并导致成年人类成红细胞以更像胎儿的表型分化。

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