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Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency

ABSTRACT: Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency

PROVIDER: PRJNA445272 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12781376.fastq.gz	Fastqsanger.gz
	SRR12781377.fastq.gz	Fastqsanger.gz
	SRR12781378.fastq.gz	Fastqsanger.gz
	SRR12781379.fastq.gz	Fastqsanger.gz
	SRR12781380.fastq.gz	Fastqsanger.gz

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Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency

Project description:The transition of pluripotent stem cells (PSCs) from primed to naïve states constitutes a prototypical example of cellular plasticity. The naïve state can be stabilized by defined chemical cocktails that block extracellular signals, notably including the MEK pathway. However, little is known regarding the underlying transcriptional mechanisms. Here, we report that the transcriptional landscape of the naïve state can be mimicked in mouse and human PSCs by stimulating transcriptional enhancers. This is attained by inhibiting the CDK8 and CDK19 kinases, which are negative regulators of Mediator, a critical component of enhancer function. Mechanistically, CDK8/19i triggers a global increase in the recruitment of RNA Pol II at promoters and enhancers, hyperactivating enhancers and their target genes. Lastly, the emergence of naïve pluripotency in the pre-implantation epiblast coincides with a marked reduction in CDK8/19 activity, and CDK8/19i blocks its subsequent developmental progression. These findings suggest that naïve pluripotency during development includes hyperactivation of enhancers and can be captured in vitro, either by blunting extracellular signaling, or by stimulating enhancer-driven transcription. These principles may apply to other cellular transitions.

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Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency [ChIP-seq]

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Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency [RNA-seq]

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Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency [RNA-Seq 2]

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Global hyperactivation of enhancers stabilizes human and mouse naïve pluripotency [RNA-seq]

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Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases

Project description:Pluripotent stem cells (PSCs) can transition between cell states in vitro, closely reflecting developmental changes in the early embryo. PSCs can be stabilized in their naive state by blocking extracellular differentiation stimuli, particularly FGF5 MEK signaling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK-signaling. Mechanistically, chemical inhibition of CDK8 and CDK19 kinases (CDK8/19i) removes their ability to repress the Mediator complex at enhancers. Thus CDK8/19i increases Mediator-driven recruitment of RNA Pol II to promoters and enhancers. This efficiently stabilizes the naive transcriptional program, and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be captured in-vitro by inhibiting extracellular FGF-MEK-signaling, or downstream, by CDK8/19i. These principles may apply to other contexts of cellular plasticity.

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Dissection of two routes to naïve pluripotency using different kinase inhibitors

Project 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.

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Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases

Project description:Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases

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