Repression by hdac3 and dax1 mediates lineage restriction of embryonic stem cells

ABSTRACT Mouse embryonic stem cells (mESCs) give rise to embryonic but not extraembryonic endoderm fates. Here, we identify the mechanism of this lineage barrier and report that the histone deacetylase Hdac3 and the corepressor Dax1 cooperatively restrict transdifferentiation of mESCs by silencing an enhancer of the extraembryonic endoderm-specifying transcription factor (TF) Gata6. This restriction is opposed by the pluripotency TFs Nr5a2 and Esrrb, which promote cell type conversion. Perturbation of the barrier extends mESC potency, and allows formation of 3D spheroids that mimic the spatial segregation of embryonic epiblast and extraembryonic endoderm in early embryos. Overall, this study shows that transcriptional repressors stabilize pluripotency by biasing the equilibrium between embryonic and extraembryonic lineages that is hardwired into the mESC TF network.