Global and Local Architecture of the Mammalian microRNA-Transcription Factor
Regulatory Network
Reut Shalgi
Weizmann Institute
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.