EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

AbstractThe first lineage specification of pluripotent mouse epiblast segregates neuroectoderm (NE) from mesoderm and endoderm (ME) by currently poorly understood mechanisms. Here we demonstrate that the induction of any ME-gene programs critically relies on the T-box (Tbx) transcription factorsEomesandBrachyurythat concomitantly repress pluripotency and NE gene programs. Tbx-deficient cells retain pluripotency and differentiate to NE lineages despite the presence of ME-inducing signals TGFβ/Nodal and WNT. Pluripotency and NE gene networks are additionally repressed by Tbx-induced ME factors, demonstrating a remarkable redundancy in program regulation to safeguard mutually exclusive lineage specification. Chromatin analyses revealed that accessibility of ME-gene enhancers depends on Tbx-binding, while NE-gene enhancers are accessible and activation-primed already at pluripotency state. This asymmetry of chromatin landscape thus explains the default differentiation of pluripotent cells to NE in the absence of ME-induction mediated through the activating and repressive functions of early Tbx factorsEomes andBrachyury.