Cooperation between HDAC3 and DAX1 mediates lineage restriction of embryonic stem cells |
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| Authors: | Daniel Olivieri,Eleonora Castelli,Yumiko K Kawamura,Panagiotis Papasaikas,Ilya Lukonin,Melanie Rittirsch,Daniel Hess,S bastien A Smallwood,Michael B Stadler,Antoine H F M Peters,Joerg Betschinger |
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| Affiliation: | 1. Friedrich Miescher Institute for Biomedical Research, Basel Switzerland ; 2. Faculty of Sciences, University of Basel, Basel Switzerland ; 3. Swiss Institute of Bioinformatics, Basel Switzerland |
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| Abstract: | Mouse embryonic stem cells (mESCs) are biased toward producing embryonic rather than extraembryonic endoderm fates. Here, we identify the mechanism of this barrier and report that the histone deacetylase Hdac3 and the transcriptional corepressor Dax1 cooperatively limit the lineage repertoire of mESCs by silencing an enhancer of the extraembryonic endoderm‐specifying transcription factor Gata6. This restriction is opposed by the pluripotency transcription factors 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 transcriptional network. |
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| Keywords: | Dax1/Nr0b1 embryonic stem cell extraembryonic endoderm Hdac3 pluripotency |
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