Critical roles of translation initiation and RNA uridylation in endogenous retroviral expression and neural differentiation in pluripotent stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129429 | GEO | 2020/06/02
REPOSITORIES: GEO
Similar Datasets
Project description:Nat1 (also known as p97/Dap5/Eif4g2) is a ubiquitously expressed cytoplasmic protein that is homologous to the C-terminal two thirds of eukaryotic translation initiation factor 4G (also known as Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mESCs) were resistant to differentiation. In the current study, we found that Nat1 and Eif4g1 share many binding proteins, such as Eif3s, Eif4s and ribosomal proteins. However, Nat1 did not bind to Eif4e or poly A binding proteins, which are critical for cap-dependent translation initiation. In contrast, Nat1 binds to Eif2s, Fmr and related proteins, and Prrc2 proteins more preferentially than does Eif4g1. We also found that Nat1-null mESCs possess a status partially similar to ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and GSK3 signaling pathways. In Nat1-null mESCs, the ERK pathway is suppressed even without inhibitors. Ribosomal profiling revealed that translation of Map3k3 and Sos1 is suppressed in the absence of Nat1. Forced expression of Map3k3 induced differentiation of Nat1-null mESCs. These data collectively showed that Nat1 is involved in translation of proteins that are required for cell differentiation.
2017-01-06 | GSE89007 | GEO
Project description:Nat1 (also known as p97/Dap5/Eif4g2) is a ubiquitously expressed cytoplasmic protein that is homologous to the C-terminal two thirds of eukaryotic translation initiation factor 4G (also known as Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mESCs) were resistant to differentiation. In the current study, we found that Nat1 and Eif4g1 share many binding proteins, such as Eif3s, Eif4s and ribosomal proteins. However, Nat1 did not bind to Eif4e or poly A binding proteins, which are critical for cap-dependent translation initiation. In contrast, Nat1 binds to Eif2s, Fmr and related proteins, and Prrc2 proteins more preferentially than does Eif4g1. We also found that Nat1-null mESCs possess a status partially similar to ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and GSK3 signaling pathways. In Nat1-null mESCs, the ERK pathway is suppressed even without inhibitors. Ribosomal profiling revealed that translation of Map3k3 and Sos1 is suppressed in the absence of Nat1. Forced expression of Map3k3 induced differentiation of Nat1-null mESCs. These data collectively showed that Nat1 is involved in translation of proteins that are required for cell differentiation.
2017-01-06 | GSE89011 | GEO
Project description:Nat1 (also known as p97/Dap5/Eif4g2) is a ubiquitously expressed cytoplasmic protein that is homologous to the c-terminal two thirds of eukaryotic translation initiation factor 4G (also known as Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mESCs) were resistant to differentiation. In the current study, we found that NAT1 and eIF4G1 share many binding proteins, such as eIF3, eIF4A and ribosomal proteins. However, NAT1did not bind to eIF4E or poly A binding proteins, which are critical for cap-dependent translation initiation. In contrast, compared to eIF4G1, NAT1 preferentially interacts with eIF2, FMR and related proteins, and especially PRRC2 family members. We also found that Nat1-null mESCs possess a transcriptional profile similar, though not identical, to ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and GSK3 signaling pathways. In Nat1-null mESCs, the ERK pathway is suppressed even without inhibitors. Ribosome profiling revealed that translation of Map3k3 and Sos1 is suppressed in the absence of Nat1. Forced expression of Map3k3 induced differentiation of Nat1-null mESCs. These data collectively showed that Nat1 is involved in translation of proteins that are required for cell differentiation.
2017-01-06 | GSE89600 | GEO
Project description:Human pluripotent stem cells (hPSCs) have been reported in naïve and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the naïve state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in naïve hPSCs and thus failed to predict biased functional differentiation. Naïve hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore naïve hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient naïve hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.
2017-04-26 | GSE95561 | GEO
Project description:Human pluripotent stem cells (hPSCs) have been reported in naïve and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the naïve state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in naïve hPSCs and thus failed to predict biased functional differentiation. Naïve hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore naïve hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient naïve hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.
2017-04-26 | GSE95503 | GEO
Project description:Human pluripotent stem cells (hPSCs) have been reported in naïve and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the naïve state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in naïve hPSCs and thus failed to predict biased functional differentiation. Naïve hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore naïve hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient naïve hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.
2017-04-26 | GSE95502 | GEO
Project description:Human pluripotent stem cells (hPSCs) have been reported in naïve and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the naïve state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in naïve hPSCs and thus failed to predict biased functional differentiation. Naïve hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore naïve hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient naïve hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.
2017-04-26 | GSE95531 | GEO
Project description:Pluripotent stem cells (PSCs) have been successfully developed in many species. However, generating bovine induced pluripotent stem cells (biPSCs) has been challenging. Here we report the generation of biPSCs by overexpression of lysine-specific demethylase 4A (KDM4A) and repro-gramming factors OCT4, SOX2, KLF4, cMYC, LIN28, and NANOG (KdOSKMLN). These biPSCs exhibited silenced transgene expression at passage 10, and had prolonged self-renewal capacity for over 70 passages. The biPSCs have flat, primed-like PSC colony morphology in combined me-dia of knockout serum replacement (KSR) and mTeSR, but switched to dome-shaped, naïve-like PSC colony morphology in mTeSR medium and 2i/LIF with single cell colonization capacity. These cells have comparable proliferation rate to the reported primed- or naïve-state human PSCs, with three-germ layer differentiation capacity and normal karyotype. Transcriptome analysis revealed a high similarity of biPSCs to reported bovine embryonic stem cells (ESCs) and embryos. The naïve-like biPSCs can be incorporated into mouse embryos, with the extended capacity of in-tegration into extra-embryonic tissues. Finally, 24.6% cloning efficiency could be achieved in nu-clear transfer (NT) experiment using late passage biPSCs as nuclear donors. Our report represents a significant advance in the establishment of bovine PSCs.
2021-09-27 | GSE180931 | GEO
Project description:Naïve and primed pluripotent states represent two different states of pluripotency. Mouse naïve pluripotent stem cells (PSCs) exhibit germline competence as determined by chimera production test and can generate all-PSC mice by tetraploid embryo complementation (TEC) test, the most stringent functional test of developmental potency. By contrast, primed PSCs fail in germline chimeras and TEC test. Unfortunately, these tests cannot be applied to characterization of developmental pluripotency of human PSCs due to ethic issue. Extensive studies demonstrated that naïve and primed pluripotent state exhibits clear epigenome differences. Here we uncover surprising differences in telomere maintenance, retrotransposon activity and genomic stability between these two pluripotent states. Although both states express high telomerase activity, naïve PSCs show robust telomere elongation capacity, associated with higher telomere recombination, consistent with sporadic expression of two-cell (2C) genes including Zscan4. Distinctively, primed PSCs only can maintain their telomere length but without elongation, in association with repression of 2C genes, and increased telomere fragility and telomeric DNA damage with passages. RNA-seq revealed that DNA repair and especially recombination repair pathways are down-regulated in primed state compared to naïve state cells, corroborating the robust DNA repair capacity and genome stability in naïve PSCs. These data suggest that vigorous telomere elongation of naïve state may act to minimize DNA damage to the genome. Furthermore, we identified LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz-int to define primed PSCs, distinguishing the two pluripotent states. Heterochromatin modifications and Dnmt3b differentially regulate transcription of the 2C genes and retrotransposons. Notably, aberrant expression of retrotransposons links to increased genomic stability of primed PSCs. Hence, our data reveals that telomere regulation and retrotransposon activity markedly distinguishes naïve from primed pluripotent state. These new criteria may facilitate induction of high quality and additional characterization of developmental pluripotency and scrutinizing the genomic stability of human naïve PSCs for regenerative medicine
2020-08-22 | GSE154487 | GEO
Project description:Naïve and primed pluripotent states represent two different states of pluripotency. Mouse naïve pluripotent stem cells (PSCs) exhibit germline competence as determined by chimera production test and can generate all-PSC mice by tetraploid embryo complementation (TEC) test, the most stringent functional test of developmental potency. By contrast, primed PSCs fail in germline chimeras and TEC test. Unfortunately, these tests cannot be applied to characterization of developmental pluripotency of human PSCs due to ethic issue. Extensive studies demonstrated that naïve and primed pluripotent state exhibits clear epigenome differences. Here we uncover surprising differences in telomere maintenance, retrotransposon activity and genomic stability between these two pluripotent states. Although both states express high telomerase activity, naïve PSCs show robust telomere elongation capacity, associated with higher telomere recombination, consistent with sporadic expression of two-cell (2C) genes including Zscan4. Distinctively, primed PSCs only can maintain their telomere length but without elongation, in association with repression of 2C genes, and increased telomere fragility and telomeric DNA damage with passages. RNA-seq revealed that DNA repair and especially recombination repair pathways are down-regulated in primed state compared to naïve state cells, corroborating the robust DNA repair capacity and genome stability in naïve PSCs. These data suggest that vigorous telomere elongation of naïve state may act to minimize DNA damage to the genome. Furthermore, we identified LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz-int to define primed PSCs, distinguishing the two pluripotent states. Heterochromatin modifications and Dnmt3b differentially regulate transcription of the 2C genes and retrotransposons. Notably, aberrant expression of retrotransposons links to increased genomic stability of primed PSCs. Hence, our data reveals that telomere regulation and retrotransposon activity markedly distinguishes naïve from primed pluripotent state. These new criteria may facilitate induction of high quality and additional characterization of developmental pluripotency and scrutinizing the genomic stability of human naïve PSCs for regenerative medicine
2020-08-22 | GSE140665 | GEO