Analysis of regulatory network topology reveals functionally distinct classes of microRNAs

Abstract

MicroRNAs (miRNAs) negatively regulate the expression of target genes at the post-transcriptional level. Little is known about the crosstalk between miRNAs and transcription factors (TFs). Here we provide data suggesting that the interaction patterns between TFs and miRNAs can influence the biological functions of miRNAs. From this global survey, we find that a regulated feedback loop, in which two TFs regulate each other and one miRNA regulates both of the factors, is the most significantly overrepresented network motif. Mathematical modeling shows that the miRNA in this motif stabilizes the feedback loop to resist environmental perturbation, providing one mechanism to explain the robustness of developmental programs that is contributed by miRNAs. Furthermore, on the basis of a network motif profile analysis, we demonstrate the existence of two classes of miRNAs with distinct network topological properties. The first class of miRNAs is regulated by a large number of TFs, whereas the second is regulated by only a few TFs. The differential expression level of the two classes of miRNAs in embryonic developmental stages versus adult tissues suggests that the two classes may have fundamentally different biological functions. Our results demonstrate that the TFs and miRNAs extensively interact with each other and the biological functions of miRNAs may be wired in the regulatory network topology.

MicroRNA (miRNA)-mediated Interaction between Leukemia/Lymphoma-related Factor (LRF) and Alternative Splicing Factor/Splicing Factor 2 (ASF/SF2) Affects Mouse Embryonic Fibroblast Senescence and Apoptosis

“…We have previously shown that the miR-20 family directs MEF toward senescence by down-regulating multiple targets (LRF, E2F1, and other unknown targets (10)), whereas other miRNA families such as miR-100 or miR-125b, which target LRF, do not have this property. 4 These findings indicate that the final biological outcome of a miRNA derives from the combinatorial effect of multiple targets (16,51). In line with this concept, we can postulate that miR-28 modulates genes other 4 G. Rainaldi, unpublished results.…”

“…There is increasing evidence that TFs and miRNAs can work cooperatively, and preliminary investigations showed that the two types of regulators tend to regulate each other; TF-encoding genes have more miRNA binding sites than other classes of protein coding genes. Vice versa, miRNA coding genes have more TFs binding sites in their promoter than, for example, structural protein coding genes (16). The action of miRNAs in concert with other regulatory processes can basically be classified in two types of miRNA-containing circuits (17).…”

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

“…17 In this context, we wondered whether miR-205 was able to directly or indirectly regulate DNp63a. Silencing of miR-205 in RWPE-1 cells resulted in a marked upregulation of DNp63a protein (Figure 3a), although its mRNA levels appeared to be slightly down-modulated (Figure 3b).…”

Functional characteristics of a double negative feedback loop mediated by microRNAs

“…The regulatory roles of miRNAs have been a subject of research for the last several years, both experimentally and theoretically (Shimoni et al 2007;Wang and Raghavachari 2011;Levine et al 2007; Levine and Hwa 2008;Mehta et al 2008;Osella et al 2011;Mitarai et al 2009;Bumgarner et al 2009;Iliopoulos et al 2009). Although some of the miRNAs have been well studied, the mechanisms of various functions and biological significance of miRNAs are still not well understood (Bumgarner et al 2009;Iliopoulos et al 2009;Tsang et al 2007;Shalgi et al 2007;Re et al 2009;Martinez et al 2008;Martinez and Walhout 2009;Yu et al 2008;Inui et al 2010;Ivey and Srivastava 2010;Johnston et al 2005;Kim 2007;Fazi 2005;Juan et al 2009;Bracken 2008;Li and Carthew 2005;Visvanathan et al 2007;Xu et al 2009;Zhao et al 2009;Pospisil 2011).…”