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

Authors: Cian J. Lynch; Raquel Bernad; Ana Martínez-Val; Marta N. Shahbazi; Sandrina Nóbrega-Pereira; Isabel Calvo; Carmen Blanco-Aparicio; +24 Authors

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

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.

Countries
France, United States, Spain, France
Keywords

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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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
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.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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OpenAIRE UsageCountsViews provided by UsageCounts
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53
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