Pluto Bioinformatics

GSE114873: Global hyperactivation of enhancers stabilizes human and mouse nave pluripotency [RNA-Seq 2]

Bulk RNA sequencing

The transition of pluripotent stem cells (PSCs) from primed to nave states constitutes a prototypical example of cellular plasticity. The nave state can be stabilized by defined chemical cocktails that block extracellular signals, notably including the MEK pathway. However, little is known regarding the underlying transcriptional mechanisms. Here, we report that the transcriptional landscape of the nave state can be mimicked in mouse and human PSCs by stimulating transcriptional enhancers. This is attained by inhibiting the CDK8 and CDK19 kinases, which are negative regulators of Mediator, a critical component of enhancer function. Mechanistically, CDK8/19i triggers a global increase in the recruitment of RNA Pol II at promoters and enhancers, hyperactivating enhancers and their target genes. Lastly, the emergence of nave pluripotency in the pre-implantation epiblast coincides with a marked reduction in CDK8/19 activity, and CDK8/19i blocks its subsequent developmental progression. These findings suggest that nave pluripotency during development includes hyperactivation of enhancers and can be captured in vitro, either by blunting extracellular signaling, or by stimulating enhancer-driven transcription. These principles may apply to other cellular transitions. SOURCE: Cian Lynch ( - Tumour Suppression Group Spanish National Cancer Research Centre (CNIO)

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