| Literature DB >> 32989249 |
Cian J Lynch1,2, Raquel Bernad1,2, Ana Martínez-Val3, Marta N Shahbazi4,5, Sandrina Nóbrega-Pereira6, Isabel Calvo1,2, Carmen Blanco-Aparicio7, Carolina Tarantino8, Elena Garreta8, Laia Richart-Ginés9, Noelia Alcazar1,2, Osvaldo Graña-Castro10, Gonzalo Gómez-Lopez10, Irene Aksoy11, Maribel Muñoz-Martín1,2, 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 Montserrat8,16,17, Pierre Savatier11, Javier Muñoz3, Magdalena Zernicka-Goetz4,18, Manuel Serrano19,20,21.
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.Entities:
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Year: 2020 PMID： 32989249 DOI： 10.1038/s41556-020-0573-1
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.213