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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.
MESH: Cell Differentiation, MESH: Signal Transduction, Pluripotent Stem Cells, 570, [SDV]Life Sciences [q-bio], ADN, MESH: Promoter Regions, 610, Stem cells, Methylation, MESH: Cyclin-Dependent Kinase 8, Mice, MESH: DNA Methylation, Genetic, Animals, Humans, MESH: Animals, Phosphorylation, Promoter Regions, Genetic, MESH: Mice, MESH: Humans, MESH: Phosphorylation, Cell Differentiation, DNA, DNA Methylation, Cyclin-Dependent Kinase 8, Cyclin-Dependent Kinases, MESH: RNA Polymerase II, [SDV] Life Sciences [q-bio], MESH: Cyclin-Dependent Kinases, Enhancer Elements, Genetic, MESH: Pluripotent Stem Cells, Female, RNA Polymerase II, Cèl·lules mare, Metilació, MESH: Female, MESH: Enhancer Elements, Signal Transduction
MESH: Cell Differentiation, MESH: Signal Transduction, Pluripotent Stem Cells, 570, [SDV]Life Sciences [q-bio], ADN, MESH: Promoter Regions, 610, Stem cells, Methylation, MESH: Cyclin-Dependent Kinase 8, Mice, MESH: DNA Methylation, Genetic, Animals, Humans, MESH: Animals, Phosphorylation, Promoter Regions, Genetic, MESH: Mice, MESH: Humans, MESH: Phosphorylation, Cell Differentiation, DNA, DNA Methylation, Cyclin-Dependent Kinase 8, Cyclin-Dependent Kinases, MESH: RNA Polymerase II, [SDV] Life Sciences [q-bio], MESH: Cyclin-Dependent Kinases, Enhancer Elements, Genetic, MESH: Pluripotent Stem Cells, Female, RNA Polymerase II, Cèl·lules mare, Metilació, MESH: Female, MESH: Enhancer Elements, Signal Transduction
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| popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network. | Top 1% | |
| influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | Top 10% | |
| impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network. | Top 1% |
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