Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition
Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition
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DOI：
10.1172/jci88936
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发表时间：
2017-06-01
影响因子：
15.9
通讯作者：
Goldfarb, Adam N.
中科院分区：
文献类型：
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作者：
Elagib, Kamaleldin E.;Lu, Chih-Huan;Goldfarb, Adam N.
伴随胎儿发育的造血转变，如红细胞珠蛋白链转换，在正常生理和疾病发展中起重要作用。在巨核细胞谱系中，人胎儿祖细胞不执行增大、多倍化和前血小板形成的成人形态发生程序。虽然这些缺陷随着妊娠期的延长而减少，但在出生时仍然足够严重，使新生儿易患血小板减少症。这些缺陷也可能导致脐带血干细胞移植后血小板回收率低下，并可能导致来自多能干细胞的巨核细胞产生血小板效率低下。在这项研究中，新生儿与成年人祖细胞的比较已经确定了专门的正转录延伸因子B（P-TEF B）激活机制，已知驱动成人巨核细胞形态发生的封锁。这种阻断是由癌胚RNA结合蛋白IGF 2BP 3的胚胎特异性表达引起的，IGF 2BP 3阻止了核RNA 7SK的不稳定，这是一个通常与成人巨核细胞P-TEFb激活相关的过程。IGF 2BP 3的敲低足以赋予新生巨核细胞成人型细胞的表型和分子特征。通过布罗莫结构域和末端外结构域（BET）抑制IGF 2BP 3表达的药理学抑制也引起新生巨核细胞的成年特征。这些结果将IGF 2BP 3鉴定为通过调节谱系特异性P-TEFb激活机制限制巨核细胞发育的人类个体发育主开关，揭示了增强血小板产生的潜在策略。
Hematopoietic transitions that accompany fetal development, such as erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors do not execute the adult morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects may also contribute to inferior platelet recovery after cord blood stem cell transplantation and may underlie inefficient platelet production by megakaryocytes derived from pluripotent stem cells. In this study, comparison of neonatal versus adult human progenitors has identified a blockade in the specialized positive transcription elongation factor b (P-TEFb) activation mechanism that is known to drive adult megakaryocyte morphogenesis. This blockade resulted from neonatal-specific expression of an oncofetal RNA-binding protein, IGF2BP3, which prevented the destabilization of the nuclear RNA 7SK, a process normally associated with adult megakaryocytic P-TEFb activation. Knockdown of IGF2BP3 sufficed to confer both phenotypic and molecular features of adult-type cells on neonatal megakaryocytes. Pharmacologic inhibition of IGF2BP3 expression via bromodomain and extraterminal domain (BET) inhibition also elicited adult features in neonatal megakaryocytes. These results identify IGF2BP3 as a human ontogenic master switch that restricts megakaryocyte development by modulating a lineage-specific P-TEFb activation mechanism, revealing potential strategies toward enhancing platelet production.