The Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate

Placental development relies on coordinated cell fate decisions governed by signalling inputs. However, little is known about how signalling cues are transformed into repressive lineage-specific transcriptional signatures. Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with the Nuclear Receptor Corepressor Complex 1 and 2 (NCoR1/2) and recruits it to key trophoblast genes. Genetic ablation of Erf or Tbl1x (a component of the NCoR1/2 complex) abrogates the Erf/NCoR1/2 interaction. This leads to mis-expression of Erf/NCor1/2 target genes resulting in a TSC differentiation defect. Mechanistically, Erf regulates expression of these genes by recruiting the NCoR1/2 complex to their enhancers and modulation of H3K27ac. Our findings uncover how the Fgf/Erf/NCoR1/2 repressive axis governs cell fate and placental development, providing a new paradigm for Fgf-mediated transcriptional control. 3'RNAseq of Erf and Tbl1x depleted (shRNA, CRISPR/Cas9 KO) and respective rescue TSCs in self-renewal conditions and differentiated for 24h by MEKi treatment (PD) or for 6 days by Fgf withdrawal (WD). ChIPseq of histone modifications and Erf/Ncor1/2 subunits in WT and KO cell lines including rescues in self-renewal conditions and differentiated for 24h by MEKi treatment (PD).