  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.
