FGF/ERK autocrine signaling induces Nanog heterogeneity, allelic switching, and differentiation in pluripotent cells, which are abolished in the naive-state (2i) by inhibition of MEK1/2 and GSK3?. Surprisingly Nanog autorepression is functional in 2i. The mechanisms activating FGF signaling and its downstream effectors leading to heterogeneity and allelic switching are unknown. We utilized genome-edited fluorescent reporter cell lines of both Nanog promotor and protein to elucidate, a NANOG

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... ced FGF autocrine signaling mediated autoregulatory mechanism. We show that Nanog autoregulation is a cell non-autonomous process initiated by NANOG, but executed by FGF/ERK. FGFR2 differentially activates autoregulation in Nanog-high cells by activating ERK1/2. pERK1/2 recruits NONO (P54nrb) to repress Nanog transcription. Collectively, we show that Nanog-induced FGF autocrine signaling mediated autoregulation is the basis of Nanog heterogeneity and allelic switching. Our data introduces an unexpected reciprocal regulatory mechanism between NANOG and FGF/ERK signaling feeding into each other's heterogeneity.