GSE99476
ERF deletion rescues RAS deficiency in mouse embryonic stem cells [ChIP-seq]
RAS proteins are key regulators of growth factor signaling. Here we show that deletion of all RAS genes in mouse embryonic stem cells (mES) leads to an overall reduction in protein translation, limits their long-term proliferative capacity and incapacitates them to differentiate. Deletion of ERF, a transcriptional repressor of the ETS family, rescues proliferation and differentiation of RAS-deficient mES cells and allows the development of teratomas lacking RAS genes. Upon RAS deletion, ERF translocates to the nucleus where it binds to multiple enhancers of key RAS targets suppressing their expression. We also reveal recurrent losses of ERF in cancer and show that ERF deficiency increases the resistance of cancer cells to pharmacological inhibition of the RAS pathway. In summary, we here reveal a central role for ERF in coordinating RAS signaling in pluripotent cells, and identify a synthetic viable interaction that bypasses the requirement for RAS proteins in mammalian cells. Overall design: We performed ChIP-seq analysis by pulling down ERF-bound genomic sequences in untreated and OHT-treated H-Ras-/-; N-Ras-/-; K-Raslox/lox; RERTert/ert ES cells. In the untreated condition ERF remains out of the nuclei by ERK-dependent phosphorylation, whereas ERF goes to the nuclei and bound its targets in the OHT-treated cells due to the absence of MAPK pathway signaling.