Dissection of the potential characteristic of miRNA-miRNA functional synergistic regulations

MicroRNAs (miRNAs), as master gene regulators, control various cellular processes through the post-transcriptional regulatory network. miRNA synergetic regulations are gradually identified by experimental or computational evidence. However, the potential characteristic underlying miRNA synergism remains a mystery. Based on the constructed miRNA-miRNA functional synergetic networks (MFSNs), we attempted to systematically dissect their potential characteristic from three levels: sequence, secondary structure and transcriptional regulation. As a result, functional synergetic miRNA pairs exhibit high seed sequence and secondary structure similarity, and these characteristics are significant even when analyzing synergism between miRNAs from different families. Additionally, synergistic miRNAs tend to share a common transcriptional regulatory mechanism. A striking property of miRNAs with both synergism and co-regulation is their central roles in the MFSN, and tends to be involved in complex diseases. The potential characteristic in these three levels are validated to be robust by analyzing different MFSNs. Finally, we identified four tightly cooperative miRNA sub-networks which are also co-regulated by transcription factors, all of which regulate many important functions, including embryonic development, oncogenesis and micromanagement of metastasis, helping us to further understand the "language" of transcriptional and post-transcriptional regulation from a cross-layer view.