MicroRNAs (miRNAs) critically modulate stem cell  pluripotency, but the fundamental mechanism remains largely unknown. This study systematically reveals the global mechanism of miRNA functions in mouse stem cells by analyzing genome-wide physical interactions between miRNAs and their targets. Generally, miRNAs primarily repress developmental processes, but surprisingly the top up-regulated miRNAs do not directly target the pluripotent core factors as thought ; they only target the signal pathways associated with pluripotency. This suggests that the most important miRNAs in stem cells may only indirectly regulate the pluripotency. Interestingly, miRNAs predominately target and repress DNA methyltransferases, the core enzymes for DNA methylation , and decreasing methylation in turn activates the top miRNAs . This system-wide circuit between up-regulated miRNAs and the repressed DNA methylation system eventually activates the pluripotent core factors for pluripotency. Therefore, miRNAs systematically repress development and inhibit the epigenetic system to dynamically modulate stem cell pluripotency .
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 .
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, 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