A NANOG‐pERK reciprocal regulatory circuit regulates Nanog autoregulation and ERK signaling dynamics

Abstract

The self‐renewal and differentiation potential of embryonic stem cells (ESCs) is maintained by the regulated expression of core pluripotency factors. Expression levels of the core pluripotency factor Nanog are tightly regulated by a negative feedback autorepression loop. However, it remains unclear how ESCs perceive NANOG levels and execute autorepression. Here, we show that a dose‐dependent induction of Fgfbp1 and Fgfr2 by NANOG activates autocrine‐mediated ERK signaling in Nanog‐high cells to trigger autorepression. pERK recruits NONO to the Nanog locus to repress transcription by preventing POL2 loading. This Nanog autorepression process establishes a self‐perpetuating reciprocal NANOG‐pERK regulatory circuit. We further demonstrate that this reciprocal regulatory circuit induces pERK heterogeneity and ERK signaling dynamics in pluripotent stem cells. Collectively our data suggest that NANOG induces Fgfr2 and Fgfbp1 to activate ERK signaling in Nanog‐high cells to establish a NANOG‐pERK reciprocal regulatory circuit. This circuit regulates ERK signaling dynamics and Nanog autoregulation in pluripotent cells.

Embryonic stem cell ERK, AKT, plus STAT3 response dynamics combinatorics are heterogeneous but NANOG state independent

“…When ESCs of sister pairs were sorted according to their NANOG levels, we did not find a significant difference in signaling behavior between NANOG low and high sisters ( Figure 4 H, right panels). Supporting our findings above and in contrast to a previous study ( Kale et al., 2022 ), this suggests that pluripotency and ERK/STAT3 dynamics are indeed independent.…”

ERK2 stimulates MYC transcription by anchoring CDK9 to the MYC promoter in a kinase activity–independent manner

“…Therefore, we posit that an important role for ERK2 in the regulation of MYC transcription would be acting as a tether to facilitate CDK9 recruitment to the MYC promoter, a task that would not require ERK2 kinase activity nor being in a phosphorylated state, notwithstanding the fact that it must be phosphorylated to translocate to the nucleus. Given that ERK can recruit repressors to the Nanog locus, impeding Pol II activation ( 49 ), ERK2 may act as an anchor at promoters to either activate or repress transcription, depending on its interaction partners.…”

Derivation of trophoblast stem cells unveils unrestrained potential of mouse ESCs and epiblast

“…We asked whether Nanog or Oct4 expression levels affect CHIR-induced expression of Cdx2 and priming of ESCs to TE during ESTS derivation. We utilised Nanog:GFP (TNGA) (Chambers et al, 2007) and Oct4:GFP (Oct4GiP) (Kale et al, 2022) ESC lines to sort the lowest 10% and highest 10% Nanog or Oct4 expressing cells. The Cdx2 transcript was analysed after 16hrs of CHIR treatment.…”