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Whsc1 links pluripotency exit with mesendoderm specification

Author(s)
Tian, Tian V.; Di Stefano, Bruno; Stik, Grégoire; Vila-Casadesús, Maria; Sardina, José Luis; Vidal, Enrique; Dasti, Alessandro; Segura-Morales, Carolina; De Andrés-Aguayo, Luisa; Gómez, Antonio; Goldmann, Johanna; Jaenisch, Rudolf; Graf, Thomas; ... Show more Show less
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Abstract
How pluripotent stem cells differentiate into the main germ layers is a key question of developmental biology. Here, we show that the chromatin-related factor Whsc1 (also known as Nsd2 and MMSET) has a dual role in pluripotency exit and germ layer specification of embryonic stem cells. On induction of differentiation, a proportion of Whsc1-depleted embryonic stem cells remain entrapped in a pluripotent state and fail to form mesendoderm, although they are still capable of generating neuroectoderm. These functions of Whsc1 are independent of its methyltransferase activity. Whsc1 binds to enhancers of the mesendodermal regulators Gata4, T (Brachyury), Gata6 and Foxa2, together with Brd4, and activates the expression of these genes. Depleting each of these regulators also delays pluripotency exit, suggesting that they mediate the effects observed with Whsc1. Our data indicate that Whsc1 links silencing of the pluripotency regulatory network with activation of mesendoderm lineages.
Date issued
2019-06
URI
https://hdl.handle.net/1721.1/121965
Department
Whitehead Institute for Biomedical Research
Journal
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Citation
Tian, Tian V. et al. "Whsc1 links pluripotency exit with mesendoderm specification." Nature Cell Biology 21 (June 2019): 824-834 © 2019 The Author(s)
Version: Author's final manuscript
ISSN
1465-7392
1476-4679
Keywords
Cell Biology

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