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Dissection of two routes to naïve pluripotency using different kinase inhibitors
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) stimul...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994667/ https://www.ncbi.nlm.nih.gov/pubmed/33767186 http://dx.doi.org/10.1038/s41467-021-22181-5 |
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author | Martinez-Val, Ana Lynch, Cian J. Calvo, Isabel Ximénez-Embún, Pilar Garcia, Fernando Zarzuela, Eduardo Serrano, Manuel Munoz, Javier |
author_facet | Martinez-Val, Ana Lynch, Cian J. Calvo, Isabel Ximénez-Embún, Pilar Garcia, Fernando Zarzuela, Eduardo Serrano, Manuel Munoz, Javier |
author_sort | Martinez-Val, Ana |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7994667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79946672021-04-16 Dissection of two routes to naïve pluripotency using different kinase inhibitors Martinez-Val, Ana Lynch, Cian J. Calvo, Isabel Ximénez-Embún, Pilar Garcia, Fernando Zarzuela, Eduardo Serrano, Manuel Munoz, Javier Nat Commun Article 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. Nature Publishing Group UK 2021-03-25 /pmc/articles/PMC7994667/ /pubmed/33767186 http://dx.doi.org/10.1038/s41467-021-22181-5 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Martinez-Val, Ana Lynch, Cian J. Calvo, Isabel Ximénez-Embún, Pilar Garcia, Fernando Zarzuela, Eduardo Serrano, Manuel Munoz, Javier Dissection of two routes to naïve pluripotency using different kinase inhibitors |
title | Dissection of two routes to naïve pluripotency using different kinase inhibitors |
title_full | Dissection of two routes to naïve pluripotency using different kinase inhibitors |
title_fullStr | Dissection of two routes to naïve pluripotency using different kinase inhibitors |
title_full_unstemmed | Dissection of two routes to naïve pluripotency using different kinase inhibitors |
title_short | Dissection of two routes to naïve pluripotency using different kinase inhibitors |
title_sort | dissection of two routes to naïve pluripotency using different kinase inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994667/ https://www.ncbi.nlm.nih.gov/pubmed/33767186 http://dx.doi.org/10.1038/s41467-021-22181-5 |
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