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The Mediator Complex – The Gateway to Naïve Pluripotency?

Review ofGlobal hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinasesfrom Nature Cell Biology by Stuart P. Atkinson

Researchers from the laboratory of Manuel Serrano (IRB, Barcelona, Spain) recently set out to elucidate the transcriptional basis of pluripotent stem cell identity and plasticity by inhibiting the CDK8/19 kinases of the Mediator complex. The authors chose these factors as the Mediator complex plays a central role in enhancer-driven transcription and may influence cellular identity and plasticity [1, 2]. Furthermore, of the thirty subunits of the Mediator complex, only the CDK8 kinase and its similar paralogue CDK19 display any enzymatic activity [3-5].

In their recent Nature Cell Biology study [6], Lynch et al. now report that the CDK8/19 Mediator components control pluripotent stem cell differentiation and self-renewal and regulate preimplantation naïve epiblast gene expression in both mice and humans. Does the mediator may represent the gateway to the naïve state of pluripotent stem cells.

The authors discovered that the chemical inhibition of CDK8 and CDK19 kinases in human and mouse pluripotent stem cells derepressed the Mediator complex at enhancers, which prompted an increase in the Mediator-driven recruitment of RNA polymerase II to promoters and enhancers. Interestingly, this mechanism efficiently stabilized the transcriptional program that supports naïve pluripotency and enhanced the self-renewal and developmental capacity of pluripotent stem cells without affecting FGF-MEK signaling or global DNA methylation. Furthermore, CDK8/CDK19 inhibition also conferred resistance to enhancer perturbation brought about by BRD4 inhibition, which decreases the ability of Mediator to recruit RNA polymerase II and pluripotency gene expression and boosts pluripotent stem cell differentiation. The authors also demonstrated that the attainment of the naïve pluripotent state during mouse embryonic development coincides with a reduction in CDK8/19 expression and decreased availability of the essential subunit cyclin C.

Overall, these findings suggest that the global hyperactivation of enhancers, as prompted by inhibiting CDK8/19 kinase activity, drives naïve pluripotency; furthermore, the delineation of this mechanism may help to solve any remaining challenges surrounding the unstable nature of human naïve pluripotent stem cell culture.

For more on the mechanisms controlling the naïve pluripotent state, stay tuned to the Stem Cells Portal!


References

  1. Hnisz D, Shrinivas K, Young RA, et al., A Phase Separation Model for Transcriptional Control. Cell 2017;169:13-23.
  2. Fant CB and Taatjes DJ, Regulatory functions of the Mediator kinases CDK8 and CDK19. Transcription 2019;10:76-90.
  3. Allen BL and Taatjes DJ, The Mediator complex: a central integrator of transcription. Nature Reviews Molecular Cell Biology 2015;16:155-166.
  4. Jeronimo C and Robert F, The Mediator Complex: At the Nexus of RNA Polymerase II Transcription. Trends in Cell Biology 2017;27:765-783.
  5. Soutourina J, Transcription regulation by the Mediator complex. Nature Reviews Molecular Cell Biology 2018;19:262-274.
  6. Lynch CJ, Bernad R, Martínez-Val A, et al., Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases. Nature Cell Biology 2020;22:1223-1238.