lncRNA UCA1在红细胞分化中的功能及机制研究

Nowadays, the worldwide shortage of blood supply and transfusion-transmitted infections lead to an increasing demand for artificial blood products. Some progress has been made for induction of cord blood hematopoietic stem/progenitor CD34+ cells to proliferate and differentiate to RBCs in vitro. However, the use of produced RBCs in vitro still faces a number of challenges, such as problems with large-scale production and the inefficient enucleation. Resolving these problems will account for a comprehensive appreciation of transcription regulatory network that determines erythroid lineage commitment and differentiation. Accumulating evidence indicates that long non-coding RNA (lncRNAs) play crucial roles during lineage differentiation. Our preliminary data show that lncRNA UCA1 is expressed dynamically during the erythroid differentiation induced from human hematopoietic progenitor CD34+ cells. Functional assays demonstrate that overexpression of UCA1 promotes the differentiation process and improves the enucleation. In this proposal, we will delineate the mechanism of UCA1 during erythroid differentiation, which in turn could help to optimize the current protocol in producing RBCs form cord blood CD34+ in vitro.

全球范围面临日益严重的“血荒”危机，解决此危机的有效途径是在体外大量诱导生成生理功能成熟的红细胞。然而，目前体外诱导红细胞分化面临着诱导细胞数量不足以及功能不成熟等难题。长非编码RNA（lncRNA）是最近发现的新转录调控因子，研究发现它们在造血各阶段谱系发育中发挥重要作用。但是lncRNA在人的红系分化过程中功能还没有进行深入具体的研究。我们前期研究发现lncRNA UCA1在人红细胞分化过程中特异表达且呈动态变化，初步功能验证发现UCA1促进人红细胞的分化，本研究将继续阐明UCA1促进红细胞分化的机制。总之，我们的研究通过阐述UCA1促进红细胞分化的调控机制，为体外规模化诱导生产具有生理功能的成熟红细胞提供理论基础。

血红素除了作为酶的辅基和血红蛋白的结构成分外，还是红细胞发育和功能的重要稳态调节因子。lncRNA可调节多种生理和病理细胞过程，而其参与血红素合成机制在很大程度上尚未被探索。本研究中我们阐明了lncRNA UCA1介导的调节人类血红素代谢的调控机制。发现UCA1的表达在人红细胞发育过程中是动态调控的，其在原红系细胞中最高表达。敲降UCA1的表达抑制了血红素的生物合成并将红细胞的分化阻滞在了原始红细胞阶段。机理分析表明，UCA1与RNA结合蛋白PTBP1相互作用，UCA1作为RNA支架将PTBP1招募到ALAS2 ALAS2 mRNA上并维持其稳定。这些结果定义了lncRNA介导的转录后机制，为血红素的生物合成过作为红细胞发育过程中的决定性因素提供了新的维度。