Dissection of two routes to naïve pluripotency using different kinase inhibitors.
Nat Commun
; 12(1): 1863, 2021 03 25.
Article
em En
| MEDLINE
| ID: mdl-33767186
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinases Ciclina-Dependentes
/
Células-Tronco Pluripotentes
/
Quinase 3 da Glicogênio Sintase
/
MAP Quinase Quinase 2
/
Quinase 8 Dependente de Ciclina
/
Células-Tronco Embrionárias Murinas
Limite:
Animals
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Espanha