Kassambara Alboukadel, Jourdan Michel, Bruyer Angélique, Robert Nicolas, Pantesco Véronique, Elemento Olivier, Klein Bernard, Moreaux Jérôme
Department of Biological Hematology, CHRU Montpellier, 34000 Montpellier, France.
Institute of Human Genetics, CNRS-UPR1142, 34000 Montpellier, France.
Nucleic Acids Res. 2017 Jun 2;45(10):5639-5652. doi: 10.1093/nar/gkx327.
MicroRNAs (miRNAs) are small noncoding RNAs that attenuate expression of their mRNA targets. Here, we developed a new method and an R package, to easily infer candidate miRNA-mRNA target interactions that could be functional during a given biological process. Using this method, we described, for the first time, a comprehensive integrated analysis of miRNAs and mRNAs during human normal plasma cell differentiation (PCD). Our results reveal 63 miRNAs with significant temporal changes in their expression during normal PCD. We derived a high-confidence network of 295 target relationships comprising 47 miRNAs and 141 targets. These relationships include new examples of miRNAs that appear to coordinately regulate multiple members of critical pathways associated with PCD. Consistent with this, we have experimentally validated a role for the miRNA-30b/c/d-mediated regulation of key PCD factors (IRF4, PRDM1, ELL2 and ARID3A). Furthermore, we found that 24 PCD stage-specific miRNAs are aberrantly overexpressed in multiple myeloma (MM) tumor plasma cells compared to their normal counterpart, suggesting that MM cells frequently acquired expression changes in miRNAs already undergoing dynamic expression modulation during normal PCD. Altogether, our analysis identifies candidate novel key miRNAs regulating networks of significance for normal PCD and malignant plasma cell biology.
微小RNA（miRNA）是一类小的非编码RNA，可减弱其mRNA靶标的表达。在此，我们开发了一种新方法和一个R软件包，以轻松推断在给定生物学过程中可能具有功能的候选miRNA-mRNA靶标相互作用。使用这种方法，我们首次描述了人类正常浆细胞分化（PCD）过程中miRNA和mRNA的全面综合分析。我们的结果显示，在正常PCD过程中，有63种miRNA的表达存在显著的时间变化。我们推导了一个由295个靶标关系组成的高可信度网络，其中包括47种miRNA和141个靶标。这些关系包括一些新的miRNA实例，它们似乎协同调节与PCD相关的关键途径的多个成员。与此一致，我们通过实验验证了miRNA-30b/c/d介导的对关键PCD因子（IRF4、PRDM1、ELL2和ARID3A）的调控作用。此外，我们发现，与正常对应物相比，24种PCD阶段特异性miRNA在多发性骨髓瘤（MM）肿瘤浆细胞中异常过表达，这表明MM细胞经常在正常PCD过程中已经经历动态表达调节的miRNA中获得表达变化。总之，我们的分析确定了调控对正常PCD和恶性浆细胞生物学具有重要意义的网络的候选新型关键miRNA。
