Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Nat Cell Biol. 2020 Oct;22(10):1223-1238. doi: 10.1038/s41556-020-0573-1. Epub 2020 Sep 28.
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.
多能干细胞 (PSCs) 在体外在细胞状态之间转换，反映了早期胚胎发育的变化。通过阻断细胞外分化刺激，特别是 FGF-MEK 信号，PSCs 可以稳定在原始状态。在这里，我们报告说，可以在不影响 FGF-MEK 信号或全局 DNA 甲基化的情况下，在人和小鼠 PSCs 中再现原始状态的多个特征。从机制上讲，化学抑制 CDK8 和 CDK19（以下简称 CDK8/19）激酶会消除它们在增强子处抑制 Mediator 复合物的能力。因此，CDK8/19 抑制会增加 Mediator 驱动的 RNA 聚合酶 II（RNA Pol II）向启动子和增强子的募集。这有效地稳定了原始转录程序，并赋予了对 BRD4 抑制的增强子扰动的抗性。此外，胚胎发育过程中的原始多能性与 CDK8/19 的减少相一致。我们得出结论，全局增强子的过度激活驱动原始多能性，这可以通过抑制 CDK8/19 激酶活性在体外实现。这些原则可能适用于其他细胞可塑性的情况。
