microRNA evolution in a human transcription factor and microRNA regulatory network.

BACKGROUND: microRNAs (miRNAs) are important cellular components. The understanding of their evolution is of critical importance for the understanding of their function. Although some specific evolutionary rules of miRNAs have been revealed, the rules of miRNA evolution in cellular networks remain largely unexplored. According to knowledge from protein-coding genes, the investigations of gene evolution in the context of biological networks often generate valuable observations that cannot be obtained by traditional approaches.

RESULTS: Here, we conducted the first systems-level analysis of miRNA evolution in a human transcription factor (TF)-miRNA regulatory network that describes the regulatory relations among TFs, miRNAs, and target genes. We found that the architectural structure of the network provides constraints and functional innovations for miRNA evolution and that miRNAs showed different and even opposite evolutionary patterns from TFs and other protein-coding genes. For example, miRNAs preferentially coevolved with their activators but not with their inhibitors. During transcription, rapidly evolving TFs frequently activated but rarely repressed miRNAs. In addition, conserved miRNAs tended to regulate rapidly evolving targets, and upstream miRNAs evolved more rapidly than downstream miRNAs.

CONCLUSIONS: In this study, we performed the first systems level analysis of miRNA evolution. The findings suggest that miRNAs have a unique evolution process and thus may have unique functions and roles in various biological processes and diseases. Additionally, the network presented here is the first TF-miRNA regulatory network, which will be a valuable platform of systems biology.