MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation
MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation
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DOI：
10.1182/blood-2008-09-179150
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发表时间：
2009-07-09
期刊：
影响因子：
20.3
通讯作者：
Lee, Benhur
中科院分区：
文献类型：
--
作者：
Hashimi, Sara T.;Fulcher, Jennifer A.;Lee, Benhur
microRNA（miRNAs，miRs）调节多种细胞事件。在这里，我们确定了调节人单核细胞来源的树突状细胞（MDDC）分化的功能性miRNA-蛋白质网络。在MDDC分化的第1、3和5天，miRNA分析显示了20种miRNA的阶段特异性差异表达。为了识别和优先考虑miRNA-蛋白质网络进行功能验证，我们开发了一种目标排序算法，该算法结合了miRNA调控网络的许多特征。该系统优先考虑miR-21、miR-34 a及其同源靶标WNT 1和JAG 1进行功能验证。通过DC-SIGN/CD 14表达比率定量，miR-21和miR-34 a两者的抑制阻止了MDDC分化，显示这些miRNA在MDDC分化中的协同参与。我们证实了WNT 1和JAG 1的3'非翻译区是这些miRNAs的功能靶点，并提供了这些靶点被抑制的证据。值得注意的是，外源性添加的Wnt-1和Jagged-1也阻止了MDDC的分化，这表明miRNA介导的内源性WNT 1和JAG 1表达的抑制对于MDDC的适当分化是重要的。最后，抑制miR-21和miR-34 a，或添加Wnt-1和Jagged-1，导致内吞能力降低，这是未成熟DC的关键功能。因此，我们的新方法鉴定并验证了一些参与表型和功能MDDC分化的miRNA-蛋白质网络。（血。2009; 114：404-414）
MicroRNAs (miRNAs, miRs) modulate a multitude of cellular events. Here, we identify functional miRNA-protein networks that regulate human monocytederived dendritic cell (MDDC) differentiation. miRNA profiling revealed stage-specific differential expression of 20 miRNAs during days 1, 3, and 5 of MDDC differentiation. To identify and prioritize miRNA-protein networks for functional validation, we developed a target ranking algorithm that incorporates many features of miRNA regulatory networks. This system prioritized miR-21, miR-34a, and their cognate targets WNT1 and JAG1 for functional validation. Inhibition of both miR-21 and miR-34a stalled MDDC differentiation, as quantified by DC-SIGN/CD14 expression ratios, showing cooperative involvement of these miRNAs in MDDC differentiation. We confirmed that the 3' untranslated regions of WNT1 and JAG1 were functional targets of these miRNAs and provide evidence that these targets were translationally suppressed. Significantly, exogenously added Wnt-1 and Jagged-1 also stalled MDDC differentiation, suggesting that miRNA-mediated inhibition of endogenous WNT1 and JAG1 expression was important for proper MDDC differentiation. Finally, inhibition of miR-21 and miR-34a, or addition of Wnt-1 and Jagged-1, led to a decrease in endocytic capacity, a key function of immature DCs. Thus, our novel approach identified and validated some miRNA-protein networks involved in phenotypic and functional MDDC differentiation. (Blood. 2009; 114: 404-414)