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

Animals Cell Differentiation Cyclin-Dependent Kinase 8 / antagonists & inhibitors Cyclin-Dependent Kinases / antagonists & inhibitors DNA Methylation Enhancer Elements, Genetic Female Humans Mice Phosphorylation Pluripotent Stem Cells / cytology Promoter Regions, Genetic RNA Polymerase II / genetics Signal Transduction

Journal

Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575

Informations de publication

Date de publication:
10 2020
Historique:
received: 02 05 2019
accepted: 07 08 2020
pubmed: 30 9 2020
medline: 15 12 2020
entrez: 29 9 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41556-020-0573-1 PMID: 32989249
pubmed: 32989249
doi: 10.1038/s41556-020-0573-1
pii: 10.1038/s41556-020-0573-1
doi:

Substances chimiques

CDK19 protein, human EC 2.7.11.22
CDK19 protein, mouse EC 2.7.11.22
Cyclin-Dependent Kinase 8 EC 2.7.11.22
Cyclin-Dependent Kinases EC 2.7.11.22
RNA Polymerase II EC 2.7.7.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1223-1238

Subventions

Organisme : Wellcome Trust
ID : 098287/Z/12/Z
Pays : United Kingdom

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Auteurs

Cian J Lynch (CJ)

Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Raquel Bernad (R)

Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Ana Martínez-Val (A)

ProteoRed-ISCIII Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Marta N Shahbazi (MN)

Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
MRC Laboratory of Molecular Biology, Biomedical Campus, Cambridge, UK.
ORCID: 0000-0002-1599-5747

Sandrina Nóbrega-Pereira (S)

Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
ORCID: 0000-0002-9652-1382

Isabel Calvo (I)

Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
ORCID: 0000-0003-4107-296X

Carmen Blanco-Aparicio (C)

Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
ORCID: 0000-0002-3249-6595

Carolina Tarantino (C)

Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.

Elena Garreta (E)

Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.

Laia Richart-Ginés (L)

Maintenance of Transcriptional Repression by Polycomb Proteins, Institut Curie, Paris, France.

Noelia Alcazar (N)

Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Osvaldo Graña-Castro (O)

Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Gonzalo Gómez-Lopez (G)

Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
ORCID: 0000-0002-4146-0551

Irene Aksoy (I)

Stem Cell and Brain Research Institute, Univ Lyon, Université Lyon 1, INSERM U1208, Bron, France.

Maribel Muñoz-Martín (M)

Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Sonia Martinez (S)

Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
ORCID: 0000-0003-2230-7794

Sagrario Ortega (S)

Transgenic Mice Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Susana Prieto (S)

IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
ORCID: 0000-0002-9746-2396

Elisabeth Simboeck (E)

IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.

Alain Camasses (A)

IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.

Camille Stephan-Otto Attolini (C)

Bioinformatics-Biostatistics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
ORCID: 0000-0001-8045-320X

Agustin F Fernandez (AF)

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.
ORCID: 0000-0002-3792-4085

Marta I Sierra (MI)

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.

Mario F Fraga (MF)

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.

Joaquin Pastor (J)

Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Daniel Fisher (D)

IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
ORCID: 0000-0002-0822-3482

Nuria Montserrat (N)

Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain.
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.

Pierre Savatier (P)

Stem Cell and Brain Research Institute, Univ Lyon, Université Lyon 1, INSERM U1208, Bron, France.

Javier Muñoz (J)

ProteoRed-ISCIII Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
ORCID: 0000-0003-3288-3496

Magdalena Zernicka-Goetz (M)

Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Division of Biology and Biological Engineering, Caltech, Pasadena, CA, USA.
ORCID: 0000-0002-7004-2471

Manuel Serrano (M)

Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. manuel.serrano@irbbarcelona.org.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. manuel.serrano@irbbarcelona.org.
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. manuel.serrano@irbbarcelona.org.
ORCID: 0000-0001-7177-9312

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Complexe médiateur › Cyclin-Dependent Kinase 8 › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Métabolisme › Phosphorylation › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › DNA-directed RNA polymerases › RNA polymerase II › Global hyperactivation of enhancers stabilizes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Global hyperactivation of enhancers stabilizes...