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Manipulating the Mediator complex to induce naïve pluripotency
Human naïve pluripotent stem cells (PSCs) represent an optimal homogenous starting point for molecular interventions and differentiation strategies. This is in contrast to the standard primed PSCs which fluctuate in identity and are transcriptionally heterogeneous. However, despite many efforts, the...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Academic Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584500/ https://www.ncbi.nlm.nih.gov/pubmed/32771524 http://dx.doi.org/10.1016/j.yexcr.2020.112215 |
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author | Lynch, Cian J. Bernad, Raquel Calvo, Isabel Serrano, Manuel |
author_facet | Lynch, Cian J. Bernad, Raquel Calvo, Isabel Serrano, Manuel |
author_sort | Lynch, Cian J. |
collection | PubMed |
description | Human naïve pluripotent stem cells (PSCs) represent an optimal homogenous starting point for molecular interventions and differentiation strategies. This is in contrast to the standard primed PSCs which fluctuate in identity and are transcriptionally heterogeneous. However, despite many efforts, the maintenance and expansion of human naïve PSCs remains a challenge. Here, we discuss our recent strategy for the stabilization of human PSC in the naïve state based on the use of a single chemical inhibitor of the related kinases CDK8 and CDK19. These kinases phosphorylate and negatively regulate the multiprotein Mediator complex, which is critical for enhancer-driven recruitment of RNA Pol II. The net effect of CDK8/19 inhibition is a global stimulation of enhancers, which in turn reinforces transcriptional programs including those related to cellular identity. In the case of pluripotent cells, the presence of CDK8/19i efficiently stabilizes the naïve state. Importantly, in contrast to previous chemical methods to induced the naïve state based on the inhibition of the FGF-MEK-ERK pathway, CDK8/19i-naïve human PSCs are chromosomally stable and retain developmental potential after long-term expansion. We suggest this could be related to the fact that CDK8/19 inhibition does not induce DNA demethylation. These principles may apply to other fate decisions. |
format | Online Article Text |
id | pubmed-7584500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Academic Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-75845002020-10-29 Manipulating the Mediator complex to induce naïve pluripotency Lynch, Cian J. Bernad, Raquel Calvo, Isabel Serrano, Manuel Exp Cell Res Article Human naïve pluripotent stem cells (PSCs) represent an optimal homogenous starting point for molecular interventions and differentiation strategies. This is in contrast to the standard primed PSCs which fluctuate in identity and are transcriptionally heterogeneous. However, despite many efforts, the maintenance and expansion of human naïve PSCs remains a challenge. Here, we discuss our recent strategy for the stabilization of human PSC in the naïve state based on the use of a single chemical inhibitor of the related kinases CDK8 and CDK19. These kinases phosphorylate and negatively regulate the multiprotein Mediator complex, which is critical for enhancer-driven recruitment of RNA Pol II. The net effect of CDK8/19 inhibition is a global stimulation of enhancers, which in turn reinforces transcriptional programs including those related to cellular identity. In the case of pluripotent cells, the presence of CDK8/19i efficiently stabilizes the naïve state. Importantly, in contrast to previous chemical methods to induced the naïve state based on the inhibition of the FGF-MEK-ERK pathway, CDK8/19i-naïve human PSCs are chromosomally stable and retain developmental potential after long-term expansion. We suggest this could be related to the fact that CDK8/19 inhibition does not induce DNA demethylation. These principles may apply to other fate decisions. Academic Press 2020-10-15 /pmc/articles/PMC7584500/ /pubmed/32771524 http://dx.doi.org/10.1016/j.yexcr.2020.112215 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lynch, Cian J. Bernad, Raquel Calvo, Isabel Serrano, Manuel Manipulating the Mediator complex to induce naïve pluripotency |
title | Manipulating the Mediator complex to induce naïve pluripotency |
title_full | Manipulating the Mediator complex to induce naïve pluripotency |
title_fullStr | Manipulating the Mediator complex to induce naïve pluripotency |
title_full_unstemmed | Manipulating the Mediator complex to induce naïve pluripotency |
title_short | Manipulating the Mediator complex to induce naïve pluripotency |
title_sort | manipulating the mediator complex to induce naïve pluripotency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584500/ https://www.ncbi.nlm.nih.gov/pubmed/32771524 http://dx.doi.org/10.1016/j.yexcr.2020.112215 |
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