An EOMES induced epigenetic deflection initiates lineage commitment at mammalian gastrulation

Summary: paragraph Different cell types are determined by cell lineage-specific transcriptional programmes and by epigenetic regulation of chromatin 1, 2 . Yet, the functional relationships between dynamically expressed transcription factors (TFs) and chromatin changes guiding lineage specification often remain elusive 3 . First mammalian embryonic lineages segregate when pluripotent cells become committed to either Mesoderm and Endoderm (ME) or Neuroectoderm (NE). NE forms by default in the absence of signalling-induced ME specification 4, 5 , resulting from global asymmetries in chromatin state favouring NE gene programme activation as recently demonstrated 6–8 . In this study, we unravel the initiation of ME lineage specification by the genome-wide, de novo formation of chromatin accessibility at ME enhancers that epigenetically deflects pluripotent cells from default NE differentiation. The Tbx TF Eomes , previously considered a transcriptional regulator, acts as global chromatin organizer that establishes ME lineage competence. EOMES recruits the canonical ATP-dependent chromatin remodelling complex SWI/SNF to broadly generate the chromatin- accessible ME enhancer landscape. This lineage competence is generated independently of ME gene transcription that fully depends on ME-inducing signalling pathways including Wnts and TGFβ/NODAL 9 . This study thus resolves the successive steps of ME lineage differentiation by globally establishing chromatin accessibility for lineage competence, followed by signal-encoded transcriptional regulation of different ME lineage-defining gene programmes.