Dissection of two routes to naïve pluripotency using different kinase inhibitors

Research output: Contribution to journalJournal articlepeer-review


  • Martinez Del Val, Ana
  • Cian J. Lynch
  • Isabel Calvo
  • Pilar Ximénez-Embún
  • Fernando Garcia
  • Eduardo Zarzuela
  • Manuel Serrano
  • Javier Munoz

Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the naïve state. Here, we use mass spectrometry to describe the molecular events (phosphoproteome, proteome, and metabolome) triggered by 2i and Cdk8/19i on ESCs. Our data reveal widespread commonalities between these two treatments, suggesting overlapping processes. We find that post-transcriptional de-repression by both 2i and Cdk8/19i might support the mitochondrial capacity of naive cells. However, proteome reprogramming in each treatment is achieved by different mechanisms. Cdk8/19i acts directly on the transcriptional machinery, activating key identity genes to promote the naïve program. In contrast, 2i stabilizes the naïve circuitry through, in part, de-phosphorylation of downstream transcriptional effectors.

Original languageEnglish
Article number1863
JournalNature Communications
Issue number1
Number of pages16
Publication statusPublished - 2021
Externally publishedYes

Number of downloads are based on statistics from Google Scholar and www.ku.dk

No data available

ID: 261510398