Activin/Nodal Signalling and NANOG Orchestrate Human Embryonic Stem Cell Fate Decisions by Controlling the H3K4me3 Chromatin Mark
Hubner, Nina C
Genes & Development
Cold Spring Harbor Laboratory Press
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Bertero, A., Madrigal, P., Galli, A., Hubner, N. C., Moreno, I., Burks, D., Brown, S., et al. (2015). Activin/Nodal Signalling and NANOG Orchestrate Human Embryonic Stem Cell Fate Decisions by Controlling the H3K4me3 Chromatin Mark. Genes & Development, 29 702-717. https://doi.org/10.1101/gad.255984.114
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.
Activin/Nodal, H3K4me3, hESCs, SMAD2/3, DPY30, NANOG
We thank Andrew Knights for the technical support and helpful discussion, and the Wellcome-Trust Sanger Institute Microarray and Next-Generation Sequencing facilities for the technical support. We also thank the Sanger Institute Mouse Genetics Projects for mouse production and genotyping. This work was supported by the European Research Council starting grant Relieve-IMDs and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre (L.V.), a British Heart Foundation Ph.D. Studentship (A.B.), a Federation of European Biochemical Societies (FEBS) long-term fellowship and EU Fp7 grant InnovaLIV (S.P.), EU Fp7 grant TissuGEN (S.M.), and Wellcome Trust grant 098051 (D.G.). A.B. conceived the research, performed and analyzed the experiments, and wrote the manuscript. P.M. computationally analyzed ChIP-seq data sets and performed statistical analyses. N.C.H., S.B., and R.A.P. provided technical support. A.G. performed embryo dissections and dysmorphology assessments. I.M. and D.B. performed teratoma assays. D.G. supervised the bioinformatics data analysis. S.P., S.M., and L.V. conceived the research and wrote the manuscript.
External DOI: https://doi.org/10.1101/gad.255984.114
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247918
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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