Systematically Dissecting the Global Mechanism of miRNA Functions in Pluripotent Stem Cells

MicroRNAs (miRNAs) critically modulate stem cell properties like pluripotency, but the fundamental mechanism remains largely unknown. This study systematically analyzes multiple-omics data and builds a systems physical network including genome-wide interactions between miRNAs and their targets to reveal the systems mechanism of miRNA functions in mouse pluripotent stem cells. Globally, miRNAs directly repress the pluripotent core factors during differentiation state. Surprisingly, during pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes. Furthermore, at pluripotent state miRNAs predominately repress DNA methyltransferases, the core enzymes for DNA methylation. The decreasing methylation repressed by miRNAs in turn activates the top miRNAs and pluripotent core factors, creating an active circuit system to modulate pluripotency. MiRNAs vary their functions with different stem cell states. While miRNAs directly repress pluripotent core factors to facilitate the differentiation during cell differentiation, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development.