Role of nuclear receptor coactivator 3 (Ncoa3) in pluripotency maintenance.

Nuclear receptors, including Esrrb, Dax1, and Nr5a2, have been shown to be involved in pluripotency maintenance. Yet, the role of their coactivators in mouse embryonic stem cells remains unexplored. Here, we demonstrated that the nuclear receptor coactivator 3 (Ncoa3) is essential for pluripotency maintenance. Knockdown of Ncoa3 not only compromises the expression of pluripotency markers but also impairs in vitro and in vivo differentiation potential of mouse ESCs. Ncoa3 binds to the Nanog promoter and recruits the histone acetyltransferase CREB binding protein (CBP) and the histone arginine methyltransferase CARM1 to activate Nanog expression. Moreover, glycogen synthase kinase 3 GSK3 signaling down-regulates the Ncoa3 protein level to suppress Nanog expression. Thus, Ncoa3 not only contributes to self-renewal by activating Nanog but also facilitates ESC differentiation as a break point to disrupt the core transcriptional circuitry of pluripotency.