Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-09-28

AUTHORS

Cian J. Lynch, Raquel Bernad, Ana Martínez-Val, Marta N. Shahbazi, Sandrina Nóbrega-Pereira, Isabel Calvo, Carmen Blanco-Aparicio, Carolina Tarantino, Elena Garreta, Laia Richart-Ginés, Noelia Alcazar, Osvaldo Graña-Castro, Gonzalo Gómez-Lopez, Irene Aksoy, Maribel Muñoz-Martín, Sonia Martinez, Sagrario Ortega, Susana Prieto, Elisabeth Simboeck, Alain Camasses, Camille Stephan-Otto Attolini, Agustin F. Fernandez, Marta I. Sierra, Mario F. Fraga, Joaquin Pastor, Daniel Fisher, Nuria Montserrat, Pierre Savatier, Javier Muñoz, Magdalena Zernicka-Goetz, Manuel Serrano

ABSTRACT

Pluripotent stem cells (PSCs) transition between cell states in vitro, reflecting developmental changes in the early embryo. PSCs can be stabilized in the naive state by blocking extracellular differentiation stimuli, particularly FGF–MEK signalling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF–MEK signalling or global DNA methylation. Mechanistically, chemical inhibition of CDK8 and CDK19 (hereafter CDK8/19) kinases removes their ability to repress the Mediator complex at enhancers. CDK8/19 inhibition therefore increases Mediator-driven recruitment of RNA polymerase II (RNA Pol II) to promoters and enhancers. This efficiently stabilizes the naive transcriptional program and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with a reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be achieved in vitro by inhibiting CDK8/19 kinase activity. These principles may apply to other contexts of cellular plasticity. More... »

PAGES

1223-1238

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  • Journal

    TITLE

    Nature Cell Biology

    ISSUE

    10

    VOLUME

    22

    Author Affiliations

  • Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
  • ProteoRed-ISCIII Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • MRC Laboratory of Molecular Biology, Biomedical Campus, Cambridge, UK
  • Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
  • Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain
  • Maintenance of Transcriptional Repression by Polycomb Proteins, Institut Curie, Paris, France
  • Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • Stem Cell and Brain Research Institute, Univ Lyon, Université Lyon 1, INSERM U1208, Bron, France
  • Transgenic Mice Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France
  • Bioinformatics-Biostatistics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
  • Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain
  • Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
  • Division of Biology and Biological Engineering, Caltech, Pasadena, CA, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41556-020-0573-1

    DOI

    http://dx.doi.org/10.1038/s41556-020-0573-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1131238304

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32989249


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