Department of Biochemistry and Molecular Biology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
Cell Res. 2011 Aug;21(8):1196-209. doi: 10.1038/cr.2011.79. Epub 2011 May 10.
Lineage differentiation is a continuous process during which fated progenitor cells execute specific programs to produce mature counterparts. This lineage-restricted pathway can be controlled by particular regulators, which are usually exclusively expressed in certain cell types or at specific differentiation stages. Here we report that miR-376a participates in the regulation of the early stages of human erythropoiesis by targeting cyclin-dependent kinase 2 (CDK2) and Argonaute 2 (Ago2). Among various human leukemia cell lines, miR-376a was only detected in K562 cells which originated from a progenitor common to the erythroid and megakaryotic lineages. Enforced expression of miR-376a or silencing of CDK2 and Ago2 by RNAi inhibits erythroid differentiation of K562 cells. Hematopoietic progenitor cells transduced with miR-376a showed a significant reduction of their erythroid clonogenic capacity. MiR-376a is relatively abundant in erythroid progenitor cells, where it reduces expression of CDK2 and maintains a low level of differentiation due to cell cycle arrest and decreased cell growth. Following erythroid induction, miR-376a is significantly down-regulated and CDK2 is released from miR-376a inhibition, thereby facilitating the escape of progenitor cells from the quiescent state into erythroid differentiation. Moreover, our results establish a functional link between miR-376a and Ago2, a key factor in miRNA biogenesis and silencing pathways with novel roles in human hematopoiesis.
谱系分化是一个连续的过程，在此过程中，定向祖细胞执行特定的程序产生成熟的对应物。这种谱系受限的途径可以被特定的调节因子控制，这些调节因子通常仅在特定的细胞类型或特定的分化阶段表达。在这里，我们报告 miR-376a 通过靶向细胞周期蛋白依赖性激酶 2（CDK2）和 Argonaute 2（Ago2）参与人类红细胞生成的早期调控。在各种人类白血病细胞系中，miR-376a 仅在起源于红细胞和巨核细胞谱系共同祖细胞的 K562 细胞中检测到。miR-376a 的强制表达或通过 RNAi 沉默 CDK2 和 Ago2 抑制 K562 细胞的红细胞分化。转导了 miR-376a 的造血祖细胞显示其红细胞集落形成能力显著降低。miR-376a 在红细胞祖细胞中含量相对丰富，它通过细胞周期阻滞和细胞生长减少来降低 CDK2 的表达并维持低分化水平。在红细胞诱导后，miR-376a 显著下调，CDK2 从 miR-376a 的抑制中释放出来，从而促进祖细胞从静止状态逃逸到红细胞分化中。此外，我们的结果在 miRNA 生物发生和沉默途径中的关键因子 Ago2 与 miR-376a 之间建立了功能联系，Ago2 在人类造血中具有新的作用。
