Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, via delle Regole, 101 38123 Mattarello (TN) Italy.
Nucleic Acids Res. 2013 Mar 1;41(5):3201-16. doi: 10.1093/nar/gkt017. Epub 2013 Feb 1.
Little is known regarding the post-transcriptional networks that control gene expression in eukaryotes. Additionally, we still need to understand how these networks evolve, and the relative role played in them by their sequence-dependent regulatory factors, non-coding RNAs (ncRNAs) and RNA-binding proteins (RBPs). Here, we used an approach that relied on both phylogenetic sequence sharing and conservation in the whole mapped 3'-untranslated regions (3'-UTRs) of vertebrate species to gain knowledge on core post-transcriptional networks. The identified human hyper conserved elements (HCEs) were predicted to be preferred binding sites for RBPs and not for ncRNAs, namely microRNAs and long ncRNAs. We found that the HCE map identified a well-known network that post-transcriptionally regulates histone mRNAs. We were then able to discover and experimentally confirm a translational network composed of RNA Recognition Motif (RRM)-type RBP mRNAs that are positively controlled by HuR, another RRM-type RBP. HuR shows a preference for these RBP mRNAs bound in stem-loop motifs, confirming its role as a 'regulator of regulators'. Analysis of the transcriptome-wide HCE distribution revealed a profile of prevalently small clusters separated by unconserved intercluster RNA stretches, which predicts the formation of discrete small ribonucleoprotein complexes in the 3'-UTRs.
关于真核生物中控制基因表达的转录后网络，我们知之甚少。此外，我们还需要了解这些网络是如何进化的，以及它们的序列依赖性调节因子、非编码 RNA（ncRNA）和 RNA 结合蛋白（RBP）在其中所起的相对作用。在这里，我们使用了一种既依赖于系统发育序列共享，又依赖于脊椎动物全映射 3'-非翻译区（3'-UTR）保守性的方法，来获得关于核心转录后网络的知识。鉴定出的人类超保守元件（HCEs）被预测为 RBP 的优先结合位点，而不是 ncRNA，即 microRNA 和长 ncRNA。我们发现，HCE 图谱确定了一个众所周知的网络，该网络在后转录水平上调节组蛋白 mRNA。然后，我们能够发现并通过实验证实一个由 RNA 识别基序（RRM）型 RBP mRNA 组成的翻译网络，该网络受另一种 RRM 型 RBP HuR 的正调控。HuR 对这些结合在茎环结构中的 RBP mRNA 表现出偏好，证实了其作为“调节因子的调节因子”的作用。对转录组范围内 HCE 分布的分析显示了一种普遍存在的小簇模式，由无保守的簇间 RNA 间隔区分开，这预测了在 3'-UTR 中离散的小核糖核蛋白复合物的形成。
