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Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening [RNA-seq]

ABSTRACT: Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening [RNA-seq]

PROVIDER: PRJNA641789 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12088421_1.fastq.gz	Fastqsanger.gz
	SRR12088421_2.fastq.gz	Fastqsanger.gz
	SRR12088422_1.fastq.gz	Fastqsanger.gz
	SRR12088422_2.fastq.gz	Fastqsanger.gz
	SRR12088423_1.fastq.gz	Fastqsanger.gz

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Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening

Project description:Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening

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Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening [WGBS]

Project description:Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening [WGBS]

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Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening [WGBS]

Project description:Background: Naïve human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional “primed” hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Methods:Here we performed high-throughput screening using a library of >3,000 well-annotated compounds to identify essential signaling requirements for naïve human pluripotency. Results:We report that MEK1/2 inhibitors can be replaced during maintenance of naïve human pluripotency by inhibitors targeting either upstream (FGFR, RAF1) or downstream (ERK1/2) kinases. Naïve hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and a transcriptional identity of the pre-implantation epiblast. In contrast, dual inhibition of MEK and ERK promotes efficient primed-to-naïve resetting in combination with PKC, ROCK, and TNKS inhibitors and Activin A. Conclusions: This work demonstrates that induction and maintenance of naïve human pluripotency are governed by distinct signaling requirements.

2021-06-15 | GSE153213 | GEO

Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening [RNA-seq]

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AMPK signaling for naïve pluripotency [Hs]

Project description:We show activation of AMP kinase (AMPK) with single chemical compounds can endow naïve pluripotency. AMPK activators reverted early-stage differentiating cells or epi-stem cells to naïve state. Moreover, AMPK activators reverted human ESCs to naïve state with pluripotent gene expression profiles and X-chromosome reactivation.

2019-03-30 | GSE92725 | GEO

AMPK signaling for naïve pluripotency [Mm]

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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.

2020-09-29 | PXD009200 | Pride

Probing the signaling requirements for naïve human pluripotency by high-throughput chemical screening

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-15 | GSE153215 | GEO

Stirred suspension bioreactors maintain naïve pluripotency of human pluripotent stem cells (hPSCs)

Project description:Although cell therapies require large numbers of quality-controlled hPSCs, existing technologies are limited in their ability to efficiently grow and scale stem cells. We report here that cell-state conversion from primed-to-naïve pluripotency enhances the biomanufacturing of hPSCs. Naïve hPSCs exhibit superior growth kinetics and aggregate formation characteristics in stirred suspension bioreactors compared to their primed counterparts. Moreover, we demonstrate the role of the bioreactor mechanical environment in the maintenance of naïve pluripotency, through transcriptomic enrichment of mechano-sensing signaling for cells in the bioreactor along with a decrease in expression of lineage-specific and primed pluripotency hallmarks. Bioreactor-cultured, naïve hPSCs express epigenetic regulatory transcripts associated with naïve pluripotency, and display hallmarks of X-chromosome reactivation. They exhibit robust production of naïve pluripotency metabolites and display reduced expression of primed pluripotency cell surface markers. We also show that these cells retain the ability to undergo targeted differentiation into beating cardiomyocytes, hepatocytes, and neural rosettes. They additionally display faster kinetics of teratoma formation compared to their primed counterparts. Naïve bioreactor hPSCs also retain structurally stable chromosomes. Our research corroborates that converting hPSCs to the naïve state enhances hPSC manufacturing and indicates a potentially important role for the bioreactor’s mechanical environment in maintaining naïve pluripotency.

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Reorganization of enhancer patterns in transition from naïve to primed pluripotency (RNA-seq)

Project description:Naïve and primed pluripotency is characterized by distinct signaling requirements, transcriptomes and developmental properties, but both cellular states share key transcriptional regulators, Oct4, Sox2 and Nanog. Here we demonstrate that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic and biochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2 and Zic2/3. Even in the absence of other differentiation cues, premature Otx2 overexpression is sufficient to exit the naïve state, induce transcription of a large subset of primed pluripotency-associated genes and redirect Oct4 to thousands of previously inaccessible sites. However, ability of Otx2 to engage new enhancer regions is determined by its levels, cis-encoded properties of the sites and signaling environment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that capacity of transcription factors such as Otx2 and Oct4 to function as pioneers is highly context-dependent transcription profile of ESCs and EpiLCs to analzye changes during differentiation and the effect of Otx2 loss and overexpression on the differentiation properties

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