Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network

• Published in: PLoS computational biology Vol. 3; no. 7; p. e131
• Main Authors: Shalgi, Reut, Lieber, Daniel, Oren, Moshe, Pilpel, Yitzhak
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2007; Public Library of Science (PLoS)
• Subjects: Algorithms; Animals; Base Sequence; Binding Sites; Computational Biology; Conserved Sequence; Feedback, Physiological; Gene expression; Gene Expression - physiology; Gene Expression Profiling; Gene Expression Regulation - genetics; Gene Regulatory Networks; Genes, Regulator - genetics; Genetics; Genetics and Genomics; Genomes; Homo (Human); Humans; Mammals; Mammals - genetics; MicroRNAs - analysis; MicroRNAs - metabolism; Promoter Regions, Genetic; Proteins; Signal Transduction - genetics; Transcription Factors - analysis; Transcription Factors - metabolism; Promoter Regions, Genetic; Gene Expression; Signal Transduction; Humans; Gene Expression Regulation; Gene Expression Profiling; Gene Regulatory Networks; Mammals; Feedback, Physiological; Algorithms; Animals; Base Sequence; MicroRNAs; Genes, Regulator; Conserved Sequence; Transcription Factors; Binding Sites
• DOI: 10.1371/journal.pcbi.0030131
• ISSN: 1553-7358; 1553-734X

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.