Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation
Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation
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DOI：
10.1038/s41588-019-0568-7
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发表时间：
2020-01-20
期刊：
影响因子：
30.8
通讯作者：
Sankaran, Vijay G.
中科院分区：
文献类型：
--
作者：
Basak, Anindita;Munschauer, Mathias;Sankaran, Vijay G.
增加胎儿血红蛋白（HbF）的产生可以改善镰状细胞病和-地中海贫血的严重程度(1)。BCL11A抑制编码HbF的基因，并通过其在发育过程中的表达变化调节人血红蛋白的转换（2-7）。然而，BCL11A发育表达的机制仍然是一个谜。本研究表明，BCL11A在人造血发育过程中受信使RNA （mRNA）翻译水平的调控。尽管在发育早期BCL11A蛋白合成减少，但BCL11A mRNA继续与核糖体相关。通过无偏倚的基因组学和蛋白质组学分析，我们证明了rna结合蛋白LIN28B在发育过程中以与BCL11A互惠的模式表达，直接与核糖体和BCL11A mRNA相互作用。此外，我们发现BCL11A mRNA翻译被LIN28B通过直接相互作用抑制，独立于其调节let-7 microrna的作用，并且BCL11A是LIN28B介导的HbF诱导的主要靶点。我们的研究结果揭示了一种以前未被认识到的人类血红蛋白转换机制，为新的治疗提供了机会。在发育中的人红细胞中的实验表明，LIN28B通过直接抑制BCL11A的翻译来控制血红蛋白的转换，而不依赖于它在调节let-7 microRNA生物发生中的作用。
Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and beta-thalassemia(1). BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development(2-7). However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.Experiments in developing human erythroid cells show that LIN28B controls hemoglobin switching by directly suppressing BCL11A translation, independently of its role in regulating let-7 microRNA biogenesis.