Abstract
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.
Highlights
MicroRNAs are short RNAs that post transcriptionally regulate messenger RNAs
It is becoming increasingly appreciated that a new type of gene which does not code for proteins, the regulatory RNAs, constitutes a considerable portion of mammalian genomes, and these genes serve as key players in the regulatory network of living cells
We investigated the potential crosstalk between the miR-mediated posttranscription layer, and the transcriptional regulation layer, whose dominant players, the transcription factors (TFs), regulate the production of protein-coding mRNAs
Summary
MicroRNAs (miRs) are short RNAs that post transcriptionally regulate messenger RNAs. Two main mechanisms for such effects are degradation of the target mRNA, and inhibition of its translation [1]. Compared with the regulation of transcription, the study of the regulatory networks spanned by miRs is only at its beginning. When it comes to transcriptional regulation, a lot is known about the main players and the interactions between them. It was found in several species that the transcription regulatory network may be decomposed into elementary building blocks, or network motifs, that recur in the network more than expected by chance, and that these motifs likely perform local ‘‘computations,’’ such as the detection of signal persistency or the coordinated gradual activation of a set of genes [17,18,19,20]
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