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Nat Cell Biol. 2019 Jul;21(7):824-834. doi: 10.1038/s41556-019-0342-1. Epub 2019 Jun 24.

Whsc1 links pluripotency exit with mesendoderm specification.

Author information

1
Center for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. tian.tian@crg.eu.
2
Center for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
3
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
4
The Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
5
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
6
Center for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. thomas.graf@crg.eu.
7
Universitat Pompeu Fabra, Barcelona, Spain. thomas.graf@crg.eu.

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.

PMID:
31235934
DOI:
10.1038/s41556-019-0342-1

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