Principles of microRNA regulation of a human cellular signaling network

Abstract

MicroRNAs (miRNAs) are endogenous approximately 22-nucleotide RNAs, which suppress gene expression by selectively binding to the 3'-noncoding region of specific messenger RNAs through base-pairing. Given the diversity and abundance of miRNA targets, miRNAs appear to functionally interact with various components of many cellular networks. By analyzing the interactions between miRNAs and a human cellular signaling network, we found that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands. In addition, when an adaptor has potential to recruit more downstream components, these components are more frequently targeted by miRNAs. This work uncovers the principles of miRNA regulation of signal transduction networks and implies a potential function of miRNAs for facilitating robust transitions of cellular response to extracellular signals and maintaining cellular homeostasis.

Figure 1

Distribution of miRNA targets in the signal network at different signaling stages. Signaling proteins are divided into four groups, for example, ligands, cell surface receptors, intracellular central signaling proteins and nuclear proteins, based on their cellular locations in the signaling pathways. The P-values were obtained by comparing the fractions of miRNA targets between each group and the whole network using randomization tests.

Figure 2

MiRNAs preferentially target the downstream components of high-link adaptors. (A) and (B) illustrate high- and low-link adaptors and their downstream components, respectively. MiRNA targets are in red.

Figure 3

Relations between the fractions of positive links and the fractions of miRNA targets in network motifs. Each type of motif was classified into several subgroups based on the number of nodes that are miRNA targets. For example, the three-node network motif may have none of their nodes as an miRNA target (category 0), or may have just one of their nodes as an miRNA target (category 1), or two (category 2) or all three as miRNA targets (category 3). The ratio of positive links to total positive and negative links in each subgroup was plotted as a function of miRNA target numbers per motif. The horizontal lines indicate the ratio of positive links to the total positive and negative links in all of the respective network motifs. The network motif ID numbering system is from Alon's motif dictionary (http://www.weizmann.ac.il/mcb/UriAlon/NetworkMotifsSW/mfinder/motifDictionary.pdf).