Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE62150 | GEO | 2014/11/24
SECONDARY ACCESSION(S): PRJNA263286
REPOSITORIES: GEO
Similar Datasets
Project description:Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers. Nonetheless, ES cells can seemingly acquire TS-like characteristics upon manipulation of lineage-determining transcription factors or activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Here we have interrogated the progression of reprogramming in ES cell models with regulatable Oct4 and Cdx2 transgenes or conditional Erk1/2 activation. Although trans-differentiation into TS-like cells is initiated, lineage conversion remains incomplete in all models, underpinned by the failure to demethylate a small group of TS cell genes. Forced expression of these non-reprogrammed genes improves trans-differentiation efficiency, but still fails to confer a stable TS cell phenotype. Thus, even ES cells in ground-state pluripotency cannot fully overcome the boundaries that separate the first cell lineages but retain an epigenetic memory of their ES cell origin.
| S-EPMC4263130 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-11-24 | E-GEOD-62150 | biostudies-arrayexpress
Project description:Reprogramming of ES cells towards the trophoblast lineage, and specifally into self-renewing TS cells, can seemingly be achieved by manipulation of transcription factors such as Cdx2 and Oct4, or modulation of signalling cascades, notably Ras signalling. Here we analyze the arising cells from such treatment in detail for the efficiency and completeness of the reprogramming process. We find that the reprogrammed cells retain an epigenetic and transcriptional memory of their ES cell origin and are not equal to bona fide trophectoderm-derived TS cells. RNA-seq expression analysis in conventional ES and TS cells and various ES-to-TS reprogramming models
2014-11-24 | E-GEOD-62149 | biostudies-arrayexpress
Project description:Reprogramming of ES cells towards the trophoblast lineage, and specifally into self-renewing TS cells, can seemingly be achieved by manipulation of transcription factors such as Cdx2 and Oct4, or modulation of signalling cascades, notably Ras signalling. Here we analyze the arising cells from such treatment in detail for the efficiency and completeness of the reprogramming process. We find that the reprogrammed cells retain an epigenetic and transcriptional memory of their ES cell origin and are not equal to bona fide trophectoderm-derived TS cells. DNA methylation analysis in conventional ES and TS cells and various ES-to-TS reprogramming models
2014-11-24 | E-GEOD-62138 | biostudies-arrayexpress
Project description:Reprogramming of ES cells towards the trophoblast lineage, and specifally into self-renewing TS cells, can seemingly be achieved by manipulation of transcription factors such as Cdx2 and Oct4, or modulation of signalling cascades, notably Ras signalling. Here we analyze the arising cells from such treatment in detail for the efficiency and completeness of the reprogramming process. We find that the reprogrammed cells retain an epigenetic and transcriptional memory of their ES cell origin and are not equal to bona fide trophectoderm-derived TS cells.
2014-11-24 | GSE62149 | GEO
Project description:Reprogramming of ES cells towards the trophoblast lineage, and specifally into self-renewing TS cells, can seemingly be achieved by manipulation of transcription factors such as Cdx2 and Oct4, or modulation of signalling cascades, notably Ras signalling. Here we analyze the arising cells from such treatment in detail for the efficiency and completeness of the reprogramming process. We find that the reprogrammed cells retain an epigenetic and transcriptional memory of their ES cell origin and are not equal to bona fide trophectoderm-derived TS cells.
2014-11-24 | GSE62138 | GEO
Project description:Genetically identical cells sharing an environment can display markedly different phenotypes. It is often unclear how much of this variation derives from chance, external signals, or attempts by individual cells to exert autonomous phenotypic programs. By observing thousands of cells for hundreds of consecutive generations under constant conditions, we dissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillus subtilis. We show that the motile state is 'memoryless', exhibiting no autonomous control over the time spent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcing coordination among related cells in the multicellular state. We show that the three-protein regulatory circuit governing the decision is modular, as initiation and maintenance of chaining are genetically separable functions. As stimulation of the same initiating pathway triggers biofilm formation, we argue that autonomous timing allows a trial commitment to multicellularity that external signals could extend.
| S-EPMC4019345 | biostudies-literature
Project description:Embryonic Stem (ES) cells are able to give rise to the three germ layers of the embryo but are prevented from contributing to the trophoblast. The molecular nature of this barrier between embryonic and trophectodermal cell fates is not clear, but is known to involve DNA methylation. Here we demonstrate that the Nucleosome Remodeling and Deacetylation (NuRD) co-repressor complex maintains the developmental barrier between embryonic and trophectodermal cell fates by maintaining transcriptional silencing of trophectoderm determinant genes in ES cells. We further show that NuRD activity facilitates DNA methylation of several of its target promoters, where it acts non-redundantly with DNA methylation to enforce transcriptional silencing. NuRD-deficient ES cells fail to completely silence expression of the trophectoderm determinant genes Elf5 and Eomes, but this alone is not sufficient to induce transdifferentiation towards the trophectoderm fate. Rather this leaves ES cells capable of activating expression of trophectoderm-specific genes in response to appropriate extracellular signals, enabling them to commit to a trophectodermal cell fate. Our findings clarify the molecular nature of the developmental barrier between the embryonic and trophoblast cell fates, and establish a role for NuRD activity in specifying sites for de novo DNA methylation.
| S-EPMC3509455 | biostudies-literature
Project description:Maternal alcohol abuse leading to fetal alcohol spectrum disorder (FASD) includes fetal growth restriction (FGR). Ethanol (EtOH) induces apoptosis of human placental trophoblast cells, possibly disrupting placentation and contributing to FGR in FASD. EtOH facilitates apoptosis in several embryonic tissues, including human trophoblasts, by raising intracellular Ca2+ . We previously found that acute EtOH exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca2+ . Therefore, nifedipine, a Ca2+ channel blocker that is commonly administered to treat preeclampsia and preterm labor, was evaluated for cytoprotective properties in trophoblast cells exposed to alcohol.Human first-trimester chorionic villous explants and the human trophoblast cell line HTR-8/SVneo (HTR) were pretreated with 12.5 to 50 nM of the Ca2+ channel blocker nifedipine for 1 hour before exposure to 50 mM EtOH for an additional hour. Intracellular Ca2+ concentrations were monitored in real time by epifluorescence microscopy, using fluo-4-AM. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), accumulation of cytoplasmic cytochrome c, and cleavage rates of caspase 3 and caspase 9.The increase in intracellular Ca2+ upon exposure to EtOH in both villous explants and HTR cells was completely blocked (p < 0.05) when pretreated with nifedipine, accompanied by inhibition of EtOH-induced release of cytochrome c, caspase activities, and TUNEL.This study indicates that nifedipine can interrupt the apoptotic pathway downstream of EtOH exposure and could provide a novel strategy for future interventions in women with fetuses at risk for FASD.
| S-EPMC5750068 | biostudies-other
Project description:BackgroundThe placenta is formed by the coordinated expansion and differentiation of trophoblast stem (TS) cells along a multi-lineage pathway. Dynamic regulation of histone 3 lysine 9 (H3K9) methylation is pivotal to cell differentiation for many cell lineages, but little is known about its involvement in trophoblast cell development.MethodsExpression of H3K9 methyltransferases was surveyed in rat TS cells maintained in the stem state and following differentiation. The role of suppressor of variegation 3-9 homolog 2 (SUV39H2) in the regulation of trophoblast cell lineage development was investigated using a loss-of-function approach in rat TS cells and ex vivo cultured rat blastocysts.ResultsAmong the twelve-known H3K9 methyltransferases, only SUV39H2 exhibited robust differential expression in stem versus differentiated TS cells. SUV39H2 transcript and protein expression were high in the stem state and declined as TS cells differentiated. Disruption of SUV39H2 expression in TS cells led to an arrest in TS cell proliferation and activation of trophoblast cell differentiation. SUV39H2 regulated H3K9 methylation status at loci exhibiting differentiation-dependent gene expression. Analyses of SUV39H2 on ex vivo rat blastocyst development supported its role in regulating TS cell expansion and differentiation. We further identified SUV39H2 as a downstream target of caudal type homeobox 2, a master regulator of trophoblast lineage development.ConclusionsOur findings indicate that SUV39H2 contributes to the maintenance of TS cells and restrains trophoblast cell differentiation.General significanceSUV39H2 serves as a contributor to the epigenetic regulation of hemochorial placental development.
| S-EPMC8052280 | biostudies-literature