miR-290/371-Mbd2-Myc circuit regulates glycolytic metabolism to promote pluripotency

Enhanced glycolysis is a main feature of pluripotent stem cells (PSCs) and is proposed to be important for the maintenance and induction of pluripotency. The molecular mechanism underlying enhanced glycolysis in PSCs is not clear. Using Dgcr8 −/− mouse embryonic stem cells (ESCs) that lack mature miRNAs, we found that miR‐290 cluster of miRNAs stimulates glycolysis by upregulating glycolytic enzymes Pkm2 and Ldha, which are also essential for the induction of pluripotency during reprogramming. Mechanistically, we identified Mbd2, a reader for methylated CpGs, as the target of miR‐290 cluster that represses glycolysis and reprogramming. Furthermore, we discovered Myc as a key target of Mbd2 that controls metabolic switch in ESCs. Importantly, we demonstrated that miR‐371 cluster, a human homolog of miR‐290 cluster, stimulates glycolysis to promote the reprogramming of human fibroblasts. Hence, we identified a previously unappreciated mechanism by which miR‐290/371 miRNAs orchestrate epigenetic, transcriptional and metabolic networks to promote pluripotency in PSCs and during reprogramming. Synopsis New data reveal a miRNA‐Mbd2‐Myc network that directly controls metabolic enzymes to govern stem cell metabolism and pluripotency. miR‐290 cluster stimulates glycolytic metabolism to promote pluripotency. miR‐290 cluster targets Mbd2 that represses glycolysis and reprogramming. Mbd2 suppresses Myc that is critical for metabolic switch in ESCs. miR‐371 cluster stimulates glycolysis to promote human somatic cell reprogramming. Graphical Abstract New data reveal a miRNA‐Mbd2‐Myc network that directly controls metabolic enzymes to govern stem cell metabolism and pluripotency.