Deciphering synergistic regulatory networks of microRNAs in hESCs and fibroblasts

MicroRNAs (miRNAs) play crucial roles in pluripotency and differentiation of human Embryonic Stem Cells (hESCs). However, synergism among multiple miRNAs and their regulatory effects on stem cells are largely unknown. We investigated the synergistic regulations among miRNAs, which are differentially expressed in hESCs and fibroblasts (Fibs) to gain deeper insights into the regulatory mechanisms of miRNA-miRNA synergism in the differentiation of hESCs into Fibs. In this study, we identified miRNA targets incorporating differential expression profiles of miRNAs and genes in hESCs-Fibs with miRNA targeting features followed by enrichment analysis. We then built the active miRNA-miRNA synergistic network (MMSN) integrating miRNA-miRNA synergistic pairs, which identified 16 miRNA-miRNA closed communities. Further, topology assessment, community overlapping and functional studies revealed hsa-miR-873-5p as an important pluripotent miRNA which might be hindering hESCs differentiation into Fibs by targeting regulators of epithelial to mesenchymal transition (EMT). On the other hand, synergism among hsa-miR-98-5p, hsa-let-7i-5p, hsa-let-7g-5p, hsa-miR-30a-3p and hsa-miR-29b-2-5p is predicted to be highly essential for promoting differentiation of hESCs in to Fibs. This study deepens our understanding of miRNA synergism and its regulatory impacts on properties of stem cells.