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An RNAi screen probing signaling control of human embryonic stem cells establishes the cell cycle-regulated restriction of the exit from pluripotency (CCNB1 overexpression)

ABSTRACT: Analysis of effect of Cyclin B1 overexpression on differentiating hESCs at the gene expression level. The hypothesis tested in the present study was that Cyclin B1 overexpression prevents the exit from pluripotency in hESCs. Results provide important information on the effect of Cyclin B1 on hESCs, such as changes in expression of TGFb-related genes and pluripotency markers, as well as mesodermic and neuroectodermic genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63215 | GEO | 2015/07/28

SECONDARY ACCESSION(S): PRJNA266997

REPOSITORIES: GEO

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An RNAi screen probing signaling control of human embryonic stem cells establishes the cell cycle-regulated restriction of the exit from pluripotency (CCNB1 overexpression)

Project description:Analysis of effect of Cyclin B1 overexpression on differentiating hESCs at the gene expression level. The hypothesis tested in the present study was that Cyclin B1 overexpression prevents the exit from pluripotency in hESCs. Results provide important information on the effect of Cyclin B1 on hESCs, such as changes in expression of TGFb-related genes and pluripotency markers, as well as mesodermic and neuroectodermic genes. Total RNA obtained from CCNB1 overexpressing hESCs incubated in medium without bFGF and TGF-beta for 0, 48 and 96 hours.

2015-07-28 | E-GEOD-63215 | biostudies-arrayexpress

An RNAi screen probing signalling control of human embryonic stem cells establishes the cell cycle-regulated restriction of the exit from pluripotency (DNA damage checkpoint)

Project description:Analysis of effect of S-phase arrest and replication checkpoint activation on differentiating hESCs at the gene expression level. The hypothesis tested in the present study was that replication checkpoint activation prevents the exit from pluripotency in hESCs. Results provide important information of the response of hESCs to replication arrest, such as upregulation of genes involved in the TGF-beta signaling pathway, and subsequent maintenance of pluripotency marker expression. Total RNA obtained from hESCs incubated in medium without bFGF and TGF-beta supplemented with either DMSO, Aphidicolin or Aphidicolin+AZD7762 for 0, 48 and 96 hours.

2015-07-28 | E-GEOD-62062 | biostudies-arrayexpress

An RNAi screen probing signalling control of human embryonic stem cells establishes the cell cycle-regulated restriction of the exit from pluripotency (DNA damage checkpoint)

2015-07-28 | GSE62062 | 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

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

2021-06-15 | GSE153212 | GEO

Saccharomyces cerevisiae

Project description:Cyclin overexpression

| PRJNA84651 | ENA

Cyclin B3 is a dominant fast-acting cyclin that drives rapid early embryonic mitoses

Project description:Mitosis in early embryos often proceeds at a rapid pace, but how this pace is achieved is not understood. Here we show that cyclin B3 is the dominant driver of rapid embryonic mitoses in the C. elegans embryo. Cyclins B1 and B2 support slow mitosis (NEBD to Anaphase ~600s) but the presence of cyclin B3 dominantly drives the ~3-fold faster mitosis observed in wildtype. Multiple mitotic events are slowed down in Cyclin B1&B2-driven mitosis and cyclin B3-associated Cdk1 H1 kinase activity is ~25-fold more active than cyclin B1-associated Cdk1. Addition of cyclin B1 to fast cyclin B3-only mitosis introduces an ~60s delay between completion of chromosome alignment and anaphase onset; this delay, which is important for segregation fidelity, is dependent on inhibitory phosphorylation of the anaphase activator Cdc20. Thus, cyclin B3 dominance, coupled to a cyclin B1-dependent delay that acts via Cdc20 phosphorylation, sets the rapid pace and ensures mitotic fidelity in the early C. elegans embryo.

2024-07-29 | PXD053811 | Pride

The functional role of OGDH for maintaining mitochondrial respiration and identity of primed human embryonic stem cells

Project description:Human embryonic stem cells (hESCs) can self-renew infinitely or differentiate into the 3 germ layer lineages in vitro with certain cues, holding great promise to model early human embryo development ex vivo. It is wildly accepted that hESCs take advantage of both glycolysis and mitochondrial respiration to favor the naïve pluripotency, while prefer glycolysis to support the primed pluripotency. Thus, the function of mitochondrial respiration in primed hESCs has been underestimated for a long time, and has not been fully understood yet. Herein, we report that the adenosine triphosphate (ATP) production rate is comparable between mitochondrial respiration and glycolysis, suggesting that mitoATP may serve as one of the major sources of the ATP pool in primed hESCs. To further reveal the function of mitochondrial respiration, we deployed inducible CRISPRi method to inhibit OGDH expression with high efficiency, resulting in the TCA cycle blockade as well as the diminishment of mitochondrial respiration activity and total ATP level. Of note, OGDH deficiency led to the exit of primed pluripotency accompanied by cell death. Furthermore, the treatment with small molecule inhibitors to block electron transport chain (ETC) can phenocopy the loss-of-function of OGDH in hESCs. Therefore, genetic and pharmacological perturbations on mitochondrial respiration can impair the stemness of primed hESCs. Collectively, the current study unveils that OGDH acts as a key regulator to fine-tune the abundance of TCA cycle metabolites to ensure the mitochondrial respiration activity in primed hESCs, and highlights the pivotal roles of mitochondrial respiration in terms of ATP production and the maintenance of primed pluripotency. Our findings may provide insights into the linkage between pluripotent states and energy metabolism in hESCs.

2022-03-03 | MTBLS4223 | MetaboLights

eIF4A3 interactome by IP-MS in mouse ESCs

Project description:RNA helicases are involved in multiple steps of RNA metabolism to direct their roles in gene expression, yet their functions in pluripotency control remain largely unexplored. Starting from an RNAi screen of RNA helicases, we identified that eIF4A3, a DEAD-box (Ddx) helicase component of the exon junction complex (EJC), is essential for the maintenance of embryonic stem cells (ESCs). We mapped the eIF4A3 interactomes in mouse ESCs, revealing that eIF4A3 is widely involved in the post-transcriptional regulation of gene expression. Mechanistically, we show that eIF4A3 post-transcriptionally controls the pluripotency-related cell cycle regulators and that its depletion causes cellular differentiation via cell cycle dysregulation. Specifically, eIF4A3 is required for the efficient nuclear export of Ccnb1 mRNA, which encodes Cyclin B1, a key component of the pluripotency-promoting pathway during cell cycle progression of ESCs. Our results reveal a previously unappreciated role of eIF4A3 and its associated EJC in the post-transcriptional cell cycle control in maintaining stem cell pluripotency.

2023-03-11 | PXD031362 | Pride

Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis

Project description:A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the “Warburg effect”, which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase. Remarkably, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased OXPHOS and increased glycolysis. In addition, we found that miR-200c-5p specifically targets SIRT2, downregulating its expression. Furthermore, SIRT2 overexpression in hPSCs significantly affected energy metabolism, altering stem cell functions such as pluripotent differentiation properties. Taken together, our results identify the miR-200c-SIRT2 axis as a key regulator of metabolic reprogramming (Warburg-like effect), via regulation of glycolytic enzymes, during human induced pluripotency and pluripotent stem cell function. To address our hypothesis that acetylation affects the metabolic switch, we compared protein acetylation in hESCs and hDFs by liquid chromatography-tandem mass spectrometry (LCMS/ MS) analyses following immunoprecipitation with acetyl-Lys antibody.

2018-10-26 | PXD006036 | Pride

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