Lin28 RNA-binding proteins play important roles in pluripotent stem cells, but 
the regulation of their expression and the mechanisms underlying their functions 
are still not definitively understood. Here we address the above-mentioned 
issues in the first steps of mouse embryonic stem cell (ESC) differentiation. We 
observed that the expression of Lin28 genes is transiently induced soon after 
the exit of ESCs from the naive ground state and that this induction is due to 
the Hmga2-dependent engagement of Otx2 with enhancers present at both Lin28 gene 
loci. These mechanisms are crucial for Lin28 regulation, as demonstrated by the 
abolishment of the Lin28 accumulation in Otx2- or Hmga2-knockout cells compared 
to the control cells. We have also found that Lin28 controls Hmga2 expression 
levels during ESC differentiation through a let-7-independent mechanism. Indeed, 
we found that Lin28 proteins bind a highly conserved element in the 3' UTR of 
Hmga2 mRNA, and this provokes a down-regulation of its translation. This 
mechanism prevents the inappropriate accumulation of Hmga2 that would modify the 
proliferation and physiological apoptosis of differentiating ESCs. In summary, 
we demonstrated that during ESC differentiation, Lin28 transient induction is 
dependent on Otx2 and Hmga2 and prevents an inappropriate excessive rise of 
Hmga2 levels.-Parisi, S., Passaro, F., Russo, L., Musto, A., Navarra, A., 
Romano, S., Petrosino, G., Russo, T. Lin28 is induced in primed embryonic stem 
cells and regulates let-7-independent events.