Metabolomics,Multiomics

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Dissection of two routes to naïve pluripotency using different kinase inhibitors


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.

OTHER RELATED OMICS DATASETS IN: PXD018694

INSTRUMENT(S): Q Exactive

SUBMITTER: Javier Munoz 

PROVIDER: MTBLS301 | MetaboLights | 2021-02-10

REPOSITORIES: MetaboLights

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Dissection of two routes to naïve pluripotency using different kinase inhibitors.

Martinez-Val Ana A   Lynch Cian J CJ   Calvo Isabel I   Ximénez-Embún Pilar P   Garcia Fernando F   Zarzuela Eduardo E   Serrano Manuel M   Munoz Javier J  

Nature communications 20210325 1


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 C  ...[more]

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