Embryonic stem cells (ESCs) are unique in that they have the capacity to 
differentiate into all of the cell types in the body. We know a lot about the 
complex transcriptional control circuits that maintain the naive pluripotent 
state under self-renewing conditions but comparatively less about how cells exit 
from this state in response to differentiation stimuli. Here, we examined the 
role of Otx2 in this process in mouse ESCs and demonstrate that it plays a 
leading role in remodeling the gene regulatory networks as cells exit from 
ground state pluripotency. Otx2 drives enhancer activation through affecting 
chromatin marks and the activity of associated genes. Mechanistically, Oct4 is 
required for Otx2 expression, and reciprocally, Otx2 is required for efficient 
Oct4 recruitment to many enhancer regions. Therefore, the Oct4-Otx2 regulatory 
axis actively establishes a new regulatory chromatin landscape during the early 
events that accompany exit from ground state pluripotency.