Shalgi Reut, Lieber Daniel, Oren Moshe, Pilpel Yitzhak
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
PLoS Comput Biol. 2007 Jul;3(7):e131. doi: 10.1371/journal.pcbi.0030131.
microRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. It is anticipated that, in combination with transcription factors (TFs), they span a regulatory network that controls thousands of mammalian genes. Here we set out to uncover local and global architectural features of the mammalian miR regulatory network. Using evolutionarily conserved potential binding sites of miRs in human targets, and conserved binding sites of TFs in promoters, we uncovered two regulation networks. The first depicts combinatorial interactions between pairs of miRs with many shared targets. The network reveals several levels of hierarchy, whereby a few miRs interact with many other lowly connected miR partners. We revealed hundreds of "target hubs" genes, each potentially subject to massive regulation by dozens of miRs. Interestingly, many of these target hub genes are transcription regulators and they are often related to various developmental processes. The second network consists of miR-TF pairs that coregulate large sets of common targets. We discovered that the network consists of several recurring motifs. Most notably, in a significant fraction of the miR-TF coregulators the TF appears to regulate the miR, or to be regulated by the miR, forming a diversity of feed-forward loops. Together these findings provide new insights on the architecture of the combined transcriptional-post transcriptional regulatory network.
微小RNA(miR)是在转录后水平调控基因表达的小RNA。据推测,它们与转录因子(TF)共同构成一个调控网络,控制着数千个哺乳动物基因。在此,我们着手揭示哺乳动物miR调控网络的局部和整体结构特征。利用人类靶标中miR进化上保守的潜在结合位点以及启动子中TF的保守结合位点,我们发现了两个调控网络。第一个网络描绘了具有许多共同靶标的miR对之间的组合相互作用。该网络揭示了几个层次结构,其中少数miR与许多其他连接较少的miR伙伴相互作用。我们发现了数百个“靶标枢纽”基因,每个基因可能受到数十个miR的大量调控。有趣的是,这些靶标枢纽基因中有许多是转录调节因子,并且它们通常与各种发育过程相关。第二个网络由共同调控大量共同靶标的miR-TF对组成。我们发现该网络由几个反复出现的基序组成。最值得注意的是,在相当一部分miR-TF共调节因子中,TF似乎调控miR,或者被miR调控,形成了多种前馈环。这些发现共同为转录 - 转录后联合调控网络的结构提供了新的见解。