Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel, Switzerland.
Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
Mol Syst Biol. 2018 Aug 27;14(8):e8266. doi: 10.15252/msb.20188266.
miRNAs are small RNAs that regulate gene expression post-transcriptionally. By repressing the translation and promoting the degradation of target mRNAs, miRNAs may reduce the cell-to-cell variability in protein expression, induce correlations between target expression levels, and provide a layer through which targets can influence each other's expression as "competing RNAs" (ceRNAs). However, experimental evidence for these behaviors is limited. Combining mathematical modeling with RNA sequencing of individual human embryonic kidney cells in which the expression of two distinct miRNAs was induced over a wide range, we have inferred parameters describing the response of hundreds of miRNA targets to miRNA induction. Individual targets have widely different response dynamics, and only a small proportion of predicted targets exhibit high sensitivity to miRNA induction. Our data reveal for the first time the response parameters of the entire network of endogenous miRNA targets to miRNA induction, demonstrating that miRNAs correlate target expression and at the same time increase the variability in expression of individual targets across cells. The approach is generalizable to other miRNAs and post-transcriptional regulators to improve the understanding of gene expression dynamics in individual cell types.
miRNAs 是一种小 RNA，可在后转录水平调节基因表达。通过抑制靶 mRNA 的翻译和促进其降解，miRNAs 可能会降低蛋白质表达的细胞间变异性，诱导靶表达水平之间的相关性，并提供一个“竞争 RNA”（ceRNA）的层面，使靶标可以相互影响对方的表达。然而，这些行为的实验证据有限。我们通过将数学建模与对两种不同 miRNA 在广泛范围内诱导的单个人类胚胎肾细胞的 RNA 测序相结合，推断了描述数百个 miRNA 靶标对 miRNA 诱导响应的参数。个别靶标具有广泛不同的反应动力学，只有一小部分预测靶标对 miRNA 诱导表现出高灵敏度。我们的数据首次揭示了整个内源性 miRNA 靶标网络对 miRNA 诱导的反应参数，表明 miRNA 相关靶标表达，同时增加了单个靶标在细胞间表达的变异性。该方法可推广到其他 miRNA 和转录后调节剂，以提高对单个细胞类型中基因表达动力学的理解。
