Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by 
the application of Yamanaka factors (OSKM), but the mechanisms underlying this 
reprogramming remain poorly understood. Here, we report that Sox2 directly 
regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation 
and that miR-29b expression is required for OSKM- and OSK-mediated 
reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo 
targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated 
with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on 
reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further 
experiments indicate that miR-29b-DNMT signaling is significantly involved in 
the regulation of DNA methylation-related reprogramming events, such as 
mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. 
Thus, our studies not only reveal that miR-29b is a novel mediator of 
reprogramming factor Sox2 but also provide evidence for a multistep mechanism in 
which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA 
methylation-related events during reprogramming.