Dissection of two routes to naïve pluripotency using different kinase inhibitors

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

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

16 Citationer (Scopus)
22 Downloads (Pure)

Abstract

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.

OriginalsprogEngelsk
Artikelnummer1863
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
Antal sider16
ISSN2041-1723
DOI
StatusUdgivet - 2021
Udgivet eksterntJa

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