Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Principles of Signalling Pathway Modulation for Enhancing Human Naïve Pluripotency Induction [WGBS]

ABSTRACT: Isolating human MEK/ERK signalling independent pluripotent stem cells (PSCs) with characteristics of naive pluripotency while maintaining differentiation competence and genetic integrity, remains challenging. Here we engineer reporter systems that allow screening for conditions that induce molecular and functional features of human naive pluripotency. Synergistic inhibition of WNT-ßCATENIN, PKC and SRC signalling enables induction of teratoma competent naïve human PSCs, with capacity to differentiate into trophoblast stem cells (TSC) and extraembryonic endodermal (XEN) cells in vitro. Divergent signalling and transcriptional requirements for boosting naïve pluripotency were found between mouse and human. P53 depletion in human naïve PSCs endows them with competitiveness to better contribute to mouse-human cross-species chimeric embryos upon priming. Finally, MEK/ERK inhibition can be substituted with inhibition for NOTCH/RBPj, which allows inducing alternative human naïve-like PSCs with diminished risk for deleterious global DNA hypomethylation. Our findings set a framework for defining the signalling foundations of human naïve pluripotency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142812 | GEO | 2021/03/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Principles of Signalling Pathway Modulation for Enhancing Human Naïve Pluripotency Induction [ChIP-seq]

Project description:Isolating human MEK/ERK signalling independent pluripotent stem cells (PSCs) with characteristics of naive pluripotency while maintaining differentiation competence and genetic integrity, remains challenging. Here we engineer reporter systems that allow screening for conditions that induce molecular and functional features of human naive pluripotency. Synergistic inhibition of WNT-ßCATENIN, PKC and SRC signalling enables induction of teratoma competent naïve human PSCs, with capacity to differentiate into trophoblast stem cells (TSC) and extraembryonic endodermal (XEN) cells in vitro. Divergent signalling and transcriptional requirements for boosting naïve pluripotency were found between mouse and human. P53 depletion in human naïve PSCs endows them with competitiveness to better contribute to mouse-human cross-species chimeric embryos upon priming. Finally, MEK/ERK inhibition can be substituted with inhibition for NOTCH/RBPj, which allows inducing alternative human naïve-like PSCs with diminished risk for deleterious global DNA hypomethylation. Our findings set a framework for defining the signalling foundations of human naïve pluripotency.

2021-03-25 | GSE125553 | GEO

Principles of Signalling Pathway Modulation for Enhancing Human Naïve Pluripotency Induction [RNA-seq]

2021-03-25 | GSE150772 | GEO

Principles of Signalling Pathway Modulation for Enhancing Human Naïve Pluripotency Induction [ATAC-Seq]

2021-03-25 | GSE124614 | GEO

Long noncoding RNA CCDC144NL-AS1 knockdown induces naïve-like state conversion of human pluripotent stem cells

Project description:Human naïve pluripotency state cells can be derived from direct isolation of inner cell mass or primed-to-naïve resetting of human embryonic stem cells (hESCs) through different combinations of transcription factors, small molecular inhibitors and growth factors. Long noncoding RNAs (lncRNAs) have been identified to be crucial in diverse biological processes, including pluripotency regulatory circuit of mouse pluripotent stem cells (PSCs), but few are involved in human PSCs’ regulation of pluripotency and naïve pluripotency derivation. This study initially planned to discover more lncRNAs possibly playing significant roles in the regulation of human PSCs’ pluripotency, but accidently identified a lncRNA whose knockdown in human PSCs induced naïve-like pluripotency conversion. The results indicated that knockdown of CCDC144NL-AS1 induces naïve-like state conversion of human PSCs in the absence of additional transcription factors or small molecular inhibitors. CCDC144NL-AS1-KD human PSCs reveal naïve-like pluripotency features, such as elevated expression of naïve pluripotency associated genes, increased developmental capacity, analogous transcriptional profiles to human naïve PSCs, and global reduction of repressive chromatin modification marks. Furthermore, CCDC144NL-AS1-KD human PSCs display inhibition of MAPK (ERK), accumulation of active β-catenin, and upregulation of some LIF/STAT3 target genes, and all of these are concordant with previous reported traits of human naïve PSCs.

2019-08-19 | GSE111929 | GEO

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.

2020-02-26 | GSE127186 | GEO

CDK8/19 small molecule inhibition promotes naïve features in human and mouse pluripotent stem cells II

2021-05-06 | GSE152378 | GEO

Human Naive Pluripotency Attained by Transient Inhibition of Mtor

Project description:The ability to support blastocyst chimera formation is the most critical property of naïve pluripotent stem cells (PSCs). Transient inhibition of mTOR converts human PSCs from primed to naive state. Naïve human PSCs cultured in 2iLI robustly incorporate into mouse embryonic development after injected to mouse blastocysts.

2020-05-13 | GSE125813 | GEO

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

Chemical conversion of human conventional Pluripotent Stem Cells to Trophoblast Stem Cells following transient naive genes activation.

Project description:In human embryos, naive pluripotent cells of the inner cell mass (ICM) generate epiblast, primitive endoderm and trophectoderm (TE) lineage, whence trophoblast cells derive. In vitro, naive pluripotent stem cells (PSCs) retain this potential and efficiently generate trophoblast stem cells (TSCs), while conventional PSCs form TSCs at low efficiency. Transient histone deacetylase and MEK inhibitions with LIF stimulation is used to chemically reset conventional to naive PSCs. Here we report that chemical resetting induces expression of both naive and TSC markers and of placental imprinted genes. A modified chemical resetting protocol allows for the fast and efficient conversion of conventional PSCs into TSCs, entailing shutdown of pluripotency genes and full activation of the trophoblast master regulators, without induction of amnion markers. Chemical resetting generates a plastic intermediate state, characterised by co-expression of naive and TSC markers, after which cells steer towards one of the two fates in response to the signalling environment. The efficiency and rapidity of our system will be useful to study cell fate transitions, and to generate models of placental disorders.

2023-01-30 | GSE184562 | GEO

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data