Author:
Bertero Alessandro,Madrigal Pedro,Galli Antonella,Hubner Nina C.,Moreno Inmaculada,Burks Deborah,Brown Stephanie,Pedersen Roger A.,Gaffney Daniel,Mendjan Sasha,Pauklin Siim,Vallier Ludovic
Abstract
Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin–SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs.
Funder
European Research Council
Cambridge Hospitals National Institute for Health Research Biomedical Research Centre
British Heart Foundation
Federation of European Biochemical Societies
EU Fp7
Wellcome Trust
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
115 articles.
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