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

doi:10.1038/s41556-020-0573-1

. 2020 Oct;22(10):1223-1238.

doi: 10.1038/s41556-020-0573-1. Epub 2020 Sep 28.

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

Cian J Lynch^{1

2}, Raquel Bernad^{1

2}, Ana Martínez-Val³, Marta N Shahbazi^{4

5}, Sandrina Nóbrega-Pereira⁶, Isabel Calvo^{1

2}, Carmen Blanco-Aparicio⁷, Carolina Tarantino⁸, Elena Garreta⁸, Laia Richart-Ginés⁹, Noelia Alcazar^{1

2}, Osvaldo Graña-Castro¹⁰, Gonzalo Gómez-Lopez¹⁰, Irene Aksoy¹¹, Maribel Muñoz-Martín^{1

2}, Sonia Martinez⁷, Sagrario Ortega¹², Susana Prieto¹³, Elisabeth Simboeck¹³, Alain Camasses¹³, Camille Stephan-Otto Attolini¹⁴, Agustin F Fernandez¹⁵, Marta I Sierra¹⁵, Mario F Fraga¹⁵, Joaquin Pastor⁷, Daniel Fisher¹³, Nuria Montserrat^{8

16

17}, Pierre Savatier¹¹, Javier Muñoz³, Magdalena Zernicka-Goetz^{4

18}, Manuel Serrano^{19

20

21}

Affiliations

¹ Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
² Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
³ ProteoRed-ISCIII Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁴ Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
⁵ MRC Laboratory of Molecular Biology, Biomedical Campus, Cambridge, UK.
⁶ Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
⁷ Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁸ Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
⁹ Maintenance of Transcriptional Repression by Polycomb Proteins, Institut Curie, Paris, France.
¹⁰ Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹¹ Stem Cell and Brain Research Institute, Univ Lyon, Université Lyon 1, INSERM U1208, Bron, France.
¹² Transgenic Mice Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹³ IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
¹⁴ Bioinformatics-Biostatistics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
¹⁵ 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.
¹⁶ Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain.
¹⁷ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
¹⁸ Division of Biology and Biological Engineering, Caltech, Pasadena, CA, USA.
¹⁹ Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. manuel.serrano@irbbarcelona.org.
²⁰ 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.
²¹ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. manuel.serrano@irbbarcelona.org.

PMID: 32989249
DOI: 10.1038/s41556-020-0573-1

Free article

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

Cian J Lynch et al. Nat Cell Biol. 2020 Oct.

Free article

. 2020 Oct;22(10):1223-1238.

doi: 10.1038/s41556-020-0573-1. Epub 2020 Sep 28.

Authors

Affiliations

¹ Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
² Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
³ ProteoRed-ISCIII Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁴ Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
⁵ MRC Laboratory of Molecular Biology, Biomedical Campus, Cambridge, UK.
⁶ Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
⁷ Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁸ Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
⁹ Maintenance of Transcriptional Repression by Polycomb Proteins, Institut Curie, Paris, France.
¹⁰ Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹¹ Stem Cell and Brain Research Institute, Univ Lyon, Université Lyon 1, INSERM U1208, Bron, France.
¹² Transgenic Mice Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹³ IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
¹⁴ Bioinformatics-Biostatistics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
¹⁵ 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.
¹⁶ Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain.
¹⁷ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
¹⁸ Division of Biology and Biological Engineering, Caltech, Pasadena, CA, USA.
¹⁹ Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. manuel.serrano@irbbarcelona.org.
²⁰ 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.
²¹ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. manuel.serrano@irbbarcelona.org.

PMID: 32989249
DOI: 10.1038/s41556-020-0573-1

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.

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References

1. Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015). - PubMed - PMC - DOI
1. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013). - PubMed - DOI
1. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013). - PubMed - PMC - DOI
1. Allen, B. L. & Taatjes, D. J. The Mediator complex: a central integrator of transcription. Nat. Rev. Mol. Cell Biol. 16, 155–166 (2015). - PubMed - PMC - DOI
1. Jeronimo, C. & Robert, F. The Mediator complex: at the nexus of RNA Polymerase II transcription. Trends Cell Biol. 27, 765–783 (2017). - PubMed - DOI

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[1] Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015). - PubMed - PMC - DOI

[2] Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015). - PubMed - PMC - DOI

[3] Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013). - PubMed - DOI

[4] Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013). - PubMed - DOI

[5] Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013). - PubMed - PMC - DOI

[6] Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013). - PubMed - PMC - DOI

[7] Allen, B. L. & Taatjes, D. J. The Mediator complex: a central integrator of transcription. Nat. Rev. Mol. Cell Biol. 16, 155–166 (2015). - PubMed - PMC - DOI

[8] Allen, B. L. & Taatjes, D. J. The Mediator complex: a central integrator of transcription. Nat. Rev. Mol. Cell Biol. 16, 155–166 (2015). - PubMed - PMC - DOI

[9] Jeronimo, C. & Robert, F. The Mediator complex: at the nexus of RNA Polymerase II transcription. Trends Cell Biol. 27, 765–783 (2017). - PubMed - DOI

[10] Jeronimo, C. & Robert, F. The Mediator complex: at the nexus of RNA Polymerase II transcription. Trends Cell Biol. 27, 765–783 (2017). - PubMed - DOI

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

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

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