Integrated Analysis of microRNA Targets Reveals New Insights into Transcriptional–Post-Transcriptional Regulatory Cross-Talk

It is becoming increasingly clear that microRNAs are key players in gene regulatory networks, modulating gene expression at post-transcriptional level. Their involvement in almost all cellular processes predicts their role in diseases, and several microRNA-based therapeutics are currently undergoing clinical testing. Despite their undeniable relevance and the substantial body of literature demonstrating their role in cancer and other pathologies, the identification of functional interactions is still challenging. To address this issue, several resources have been developed to collect information from the literature, according to different criteria and reliability scores. In the present study, we have constructed a network of verified microRNA-mRNA interactions by integrating strong-evidence couples from different resources. Our analysis of the resulting network reveals that only one-fifth of the human genes exhibits experimental validated regulation by microRNAs. A very small subset of them is controlled by more than 20 microRNAs, and these hubs are highly enriched of pivotal transcription factors and regulatory proteins, strongly suggesting a complex interplay and a combinatorial effect between transcriptional and post-transcriptional gene control. Data analysis also reveals that several microRNAs control multiple targets involved in the same pathway or biological process, likely contributing to the coordinated control of the protein levels.