Differential ERK activity shapes the epiblast methylome influencing cell-context response to germ-layer differentiation signals.

Abstract Stem cells hold promise in regenerative medicine as they have the potency to differentiate into a variety of specialized cell types. However, mechanisms underlying stem cell plasticity and lineage acquisition remain elusive. Epigenetic modifications and genome accessibility prime cellular feedback to signalling cues affecting differentiation plasticity and cell fate acquisition. Deciphering how this epigenetic code influences the context-dependent response of pluripotent cells to differentiation cues will elucidate how mammalian tissue diversity is established. Using ERK-deficient in vitro and in vivo models, we show that ERK-driven lineage-specific epigenetic signatures precede transcriptional activation of germ layer differentiation programs. We provide evidence that while distinct chromatin accessibility and methylome states prime BMP-dependent fate decisions, DNA methylation but not chromatin accessibility safeguards WNT response in the epiblast. This study establishes that ERK-driven epigenetic machinery balances epiblast plasticity and canalization, allowing context-specific spatiotemporal responses to promiscuously used signalling cues controlling organogenesis and cancers.