School of Life Sciences, Tsinghua University, Beijing, People's Republic of China.
PLoS One. 2010 Oct 22;5(10):e13558. doi: 10.1371/journal.pone.0013558.
MicroRNAs play important roles in various biological processes involving fairly complex mechanism. Analysis of genome-wide miRNA microarray demonstrate that a single miRNA can regulate hundreds of genes, but the regulative extent on most individual genes is surprisingly mild so that it is difficult to understand how a miRNA provokes detectable functional changes with such mild regulation.
To explore the internal mechanism of miRNA-mediated regulation, we re-analyzed the data collected from genome-wide miRNA microarray with bioinformatics assay, and found that the transfection of miR-181b and miR-34a in Hela and HCT-116 tumor cells regulated large numbers of genes, among which, the genes related to cell growth and cell death demonstrated high Enrichment scores, suggesting that these miRNAs may be important in cell growth and cell death. MiR-181b induced changes in protein expression of most genes that were seemingly related to enhancing cell growth and decreasing cell death, while miR-34a mediated contrary changes of gene expression. Cell growth assays further confirmed this finding. In further study on miR-20b-mediated osteogenesis in hMSCs, miR-20b was found to enhance osteogenesis by activating BMPs/Runx2 signaling pathway in several stages by co-repressing of PPARγ, Bambi and Crim1.
With its multi-target characteristics, miR-181b, miR-34a and miR-20b provoked detectable functional changes by co-regulating functionally-related gene groups or several genes in the same signaling pathway, and thus mild regulation from individual miRNA targeting genes could have contributed to an additive effect. This might also be one of the modes of miRNA-mediated gene regulation.
MicroRNAs 在涉及相当复杂机制的各种生物过程中发挥着重要作用。全基因组 miRNA 微阵列分析表明，单个 miRNA 可以调控数百个基因，但对大多数单个基因的调控程度却出人意料地温和，因此很难理解 miRNA 如何通过如此温和的调控引发可检测的功能变化。
为了探索 miRNA 介导的调控的内在机制，我们使用生物信息学方法重新分析了全基因组 miRNA 微阵列收集的数据，发现 miR-181b 和 miR-34a 在 Hela 和 HCT-116 肿瘤细胞中的转染可调节大量基因，其中与细胞生长和细胞死亡相关的基因表现出高富集分数，这表明这些 miRNA 可能在细胞生长和细胞死亡中起重要作用。MiR-181b 诱导大多数基因的蛋白表达发生变化，这些基因似乎与增强细胞生长和减少细胞死亡有关，而 miR-34a 介导的基因表达则相反。细胞生长实验进一步证实了这一发现。在进一步研究 miR-20b 在 hMSCs 中的成骨作用时，发现 miR-20b 通过共抑制 PPARγ、Bambi 和 Crim1，在几个阶段激活 BMPs/Runx2 信号通路，从而增强成骨作用。
MiR-181b、miR-34a 和 miR-20b 具有多靶点特征，通过共同调控功能相关基因群或同一信号通路中的几个基因，引起可检测的功能变化，因此单个 miRNA 靶向基因的温和调控可能促成了累加效应。这可能也是 miRNA 介导基因调控的模式之一。
