Trinidad-Barnech Juan Manuel, Fort Rafael Sebastián, Trinidad Barnech Guillermo, Garat Beatriz, Duhagon María Ana
Sección Genómica Funcional, Facultad de Ciencias, UDELAR, Iguá 4225, Montevideo 11400, Uruguay.
Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay.
Noncoding RNA. 2023 Feb 13;9(1):15. doi: 10.3390/ncrna9010015.
MicroRNAs are small RNAs that regulate gene expression through complementary base pairing with their target mRNAs. A substantial understanding of microRNA target recognition and repression mechanisms has been reached using diverse empirical and bioinformatic approaches, primarily in vitro biochemical or cell culture perturbation settings. We sought to determine if rules of microRNA target efficacy could be inferred from extensive gene expression data of human tissues. A transcriptome-wide assessment of all the microRNA-mRNA canonical interactions' efficacy was performed using a normalized Spearman correlation (Z-score) between the abundance of the transcripts in the PRAD-TCGA dataset tissues (RNA-seq mRNAs and small RNA-seq for microRNAs, 546 samples). Using the Z-score of correlation as a surrogate marker of microRNA target efficacy, we confirmed hallmarks of microRNAs, such as repression of their targets, the hierarchy of preference for gene regions (3'UTR > CDS > 5'UTR), and seed length (6 mer < 7 mer < 8 mer), as well as the contribution of the 3'-supplementary pairing at nucleotides 13-16 of the microRNA. Interactions mediated by 6 mer + supplementary showed similar inferred repression as 7 mer sites, suggesting that the 6 mer + supplementary sites may be relevant in vivo. However, aggregated 7 mer-A1 seeds appear more repressive than 7 mer-m8 seeds, while similar when pairing possibilities at the 3'-supplementary sites. We then examined the 3'-supplementary pairing using 39 microRNAs with Z-score-inferred repressive 3'-supplementary interactions. The approach was sensitive to the offset of the bridge between seed and 3'-supplementary pairing sites, and the pattern of offset-associated repression found supports previous findings. The 39 microRNAs with effective repressive 3'supplementary sites show low GC content at positions 13-16. Our study suggests that the transcriptome-wide analysis of microRNA-mRNA correlations may uncover hints of microRNA targeting determinants. Finally, we provide a bioinformatic tool to identify microRNA-mRNA candidate interactions based on the sequence complementarity of the seed and 3'-supplementary regions.
微小RNA是一类小RNA，通过与靶标mRNA进行互补碱基配对来调控基因表达。利用多种经验性和生物信息学方法，主要是体外生化或细胞培养扰动实验，人们对微小RNA靶标识别和抑制机制有了相当深入的了解。我们试图确定能否从人类组织的大量基因表达数据中推断出微小RNA靶标效应的规律。使用PRAD-TCGA数据集组织中（RNA测序的mRNA和微小RNA的小RNA测序，共546个样本）转录本丰度之间的标准化斯皮尔曼相关性（Z分数），对所有微小RNA-mRNA典型相互作用的效应进行了全转录组评估。使用相关性的Z分数作为微小RNA靶标效应的替代指标，我们证实了微小RNA的一些特征，如对其靶标的抑制作用、对基因区域的偏好层次（3'UTR > CDS > 5'UTR）、种子长度（6聚体 < 7聚体 < 8聚体），以及微小RNA第13 - 16位核苷酸处3'端互补配对的作用。由6聚体 + 互补配对介导的相互作用显示出与7聚体位点相似的推断抑制作用，这表明6聚体 + 互补配对位点在体内可能具有相关性。然而，聚集的7聚体 - A1种子似乎比7聚体 - m8种子的抑制作用更强，而在3'端互补位点的配对可能性相同时则表现相似。然后，我们使用39个具有Z分数推断的抑制性3'端互补相互作用的微小RNA，研究了3'端互补配对情况。该方法对种子和3'端互补配对位点之间桥接的偏移很敏感，并且发现的偏移相关抑制模式支持了先前的研究结果。具有有效抑制性3'端互补位点的39个微小RNA在第13 - 16位显示出低GC含量。我们的研究表明，对微小RNA - mRNA相关性进行全转录组分析可能会揭示微小RNA靶向决定因素的线索。最后，我们提供了一个生物信息学工具，用于基于种子和3'端互补区域的序列互补性来识别微小RNA - mRNA候选相互作用。
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