Activin/nodal Signaling and NANOG Orchestrate Human Embryonic Stem Cell Fate Decisions by Controlling the H3K4me3 Chromatin Mark

Genes Dev. 2015 Apr 1;29(7):702-17. doi: 10.1101/gad.255984.114. Epub 2015 Mar 24.

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.

Keywords: Activin/Nodal; DPY30; H3K4me3; NANOG; SMAD2/3; hESCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism*
  • Animals
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Embryo, Mammalian
  • Embryonic Stem Cells
  • Epigenesis, Genetic / genetics
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mice
  • Nanog Homeobox Protein
  • Nodal Protein / metabolism*
  • Signal Transduction*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism

Substances

  • Chromatin
  • Histones
  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Nodal Protein
  • Smad2 Protein
  • Smad3 Protein
  • Activins
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase