Model for regulatory shift from HBE to ASE during epiblast maturation.

(A) In the late preimplantation epiblast and in ES cells, pluripotency factors (mainly Oct4) and Nodal/Activin signaling activate HBE, which up-regulates Nodal. However, Nanog bound on HBE represses ASE so that expression levels of Nodal remain low. (B) In the postimplantation epiblast and in EpiSCs, changes in the combination of HBE-bound factors allow ASE to take over from HBE as the predominant enhancer driving Nodal expression, and the positive regulatory loop between Nodal and ASE is established, leading to higher expression levels.