ArticleNature cell biology2020
Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases.
Article in Nature cell biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 64 citations in OpenAlex.
- Inhibition of cyclin-dependent kinase 8 modulates chondrocyte transition to hypertrophy and provides in vivo protection against spontaneous osteoarthritis.Bone research · 2026Article
- CDK8 Inhibition Releases the Muscle Differentiation Block in Fusion-driven Alveolar Rhabdomyosarcoma.Cancer discovery · 2026Article
- Slow RNAPII elongation enhances naive pluripotency rewiring while maintaining high replication fork speed.Science advances · 2026Article
- Progress in stem cell-based embryo models and their applications in developmental biology and biomedicine.Nature reviews. Molecular cell biology · 2026Review
- UTERINE FIBROIDS.Physiological reviews · 2025Review
- Integrin β1 activity controls colony morphology during human pluripotent stem cell state transitions.Stem cell reports · 2025Article
- Pluripotent stem cell-derived extracellular vesicles for systemic immune modulation in diabetes therapy.Research square · 2025Article
- Med12 cooperates with multiple differentiation signals to facilitate efficient lineage transitions in embryonic stem cells.Journal of cell science · 2025Article
- Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.Journal of molecular medicine (Berlin, Germany) · 2025Article
- Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.Research square · 2024Article
- Cdk8 and Hira mutations trigger X chromosome elimination in naive female hybrid mouse embryonic stem cells.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2024Article
- Single-cell 3D genome structure reveals distinct human pluripotent states.Genome biology · 2024Article
- Hallmarks of totipotent and pluripotent stem cell states.Cell stem cell · 2024Review
- An expedition in the jungle of pluripotent stem cells of non-human primates.Stem cell reports · 2023Review
- CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins.Nucleic acids research · 2023Article
- ZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells.Nature communications · 2023Article
- CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium.EMBO reports · 2023Article
- An shRNA kinase screen identifies regulators of UHRF1 stability and activity in mouse embryonic stem cells.Epigenetics · 2022Article
- The Mediator complex as a master regulator of transcription by RNA polymerase II.Nature reviews. Molecular cell biology · 2022Review
Corrections and comments
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Authors and funding
31 authors at 11 institutions in 5 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.