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Manipulating the Mediator complex to induce naïve pluripotency.pdf (3.29 MB)

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2020-08-06

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cc-by (c) Lynch et al., 2020
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/170450

Manipulating the Mediator complex to induce naïve pluripotency

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Recurs relacionat

https://doi.org/10.1016/j.yexcr.2020.112215

Resum

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 ef ciently 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.

Matèries

Cèl·lules mare embrionàries, Transformació cel·lular, Cèl·lules mare

Matèries (anglès)

Embryonic stem cells, Cell transformation, Stem cells

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Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

Citació

LYNCH, Cian j., BERNAD, Raquel, CALVO SERRANO, Isabel, SERRANO MARUGÁN, Manuel. Manipulating the Mediator complex to induce naïve pluripotency. _Revista_. 2020. Vol. 395, núm. 2, pàgs. 112215. [consulta: 22 de gener de 2026]. [Disponible a: https://hdl.handle.net/2445/170450]

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