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Cooperation between HDAC3 and DAX1 mediates lineage restriction of embryonic stem cells
Author(s) -
Olivieri Daniel,
Castelli Eleonora,
Kawamura Yumiko K,
Papasaikas Panagiotis,
Lukonin Ilya,
Rittirsch Melanie,
Hess Daniel,
Smallwood Sébastien A,
Stadler Michael B,
Peters Antoine H F M,
Betschinger Joerg
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106818
Subject(s) - classics , library science , philosophy , history , computer science
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.