title: Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark.
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.
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
authors: Alessandro
authors: A
authors: Bertero
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors: Pedro
authors: P
authors: Madrigal
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors: Antonella
authors: A
authors: Galli
authors: Department of Molecular Biology, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands;
authors: Nina C
authors: NC
authors: Hubner
authors: Laboratory of Molecular Endocrinology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Inmaculada
authors: I
authors: Moreno
authors: Laboratory of Molecular Endocrinology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Deborah
authors: D
authors: Burks
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
authors: Stephanie
authors: S
authors: Brown
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
authors: Roger A
authors: RA
authors: Pedersen
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors: Daniel
authors: D
authors: Gaffney
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
authors: Sasha
authors: S
authors: Mendjan
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
authors: Siim
authors: S
authors: Pauklin
authors: Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; lv225@cam.ac.uk.
authors: Ludovic
authors: L
authors: Vallier
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells; D044127:Epigenesis, Genetic / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein; D055457:Nodal Protein / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D055457:Nodal Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D028341:Activins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Activin/Nodal; DPY30; H3K4me3; NANOG; SMAD2/3; hESCs