Whsc1 Links Pluripotency Exit With Mesendoderm Specification

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 (Nsd2, MMSET) has a dual role in pluripotency exit and germ layer specification of embryonic stem cells (ESCs). Upon induction of differentiation, a proportion of Whsc1-depleted ESCs 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 genes’ expression. 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.