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β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE123692 | GEO | 2020/07/01

REPOSITORIES: GEO

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Similar Datasets

β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus.

Project description:Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that β-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

| S-EPMC7439582 | biostudies-literature

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [GRO-seq]

Project description:Mouse embryonic stem cells (ESCs) cultured with MEK and GSK3 inhibitors (2i) more closely resemble the inner cell mass of pre-implantation blastocysts than those cultured with serum/LIF (SL). The transcriptional mechanisms governing this pluripotent ground state are yet unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. Here, we show that β-catenin, stabilized by GSK3 inhibition in 2i, supplies transcriptional co-regulators including BRD4, CDK9, Mediator, Cohesin, and p300 at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin and, thus, proliferation/self-renewal are still tightly controlled by the Pol2 pause release mechanism under 2i conditions. Our findings help to explain how pluripotency is preserved in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other biological contexts.

2020-07-01 | GSE140340 | GEO

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [RNA-seq]

Project description:Mouse embryonic stem cells (ESCs) cultured with inhibitors of MEK and GSK3 (2iL) more closely resemble the pre-implantation embryo inner cell mass than cultures in serum/LIF (SL). Unveiling the differences between both systems is important for understanding development and could also assist in isolating an ESC equivalent for other mammalian species. In SL, pluripotency and cell cycle gene transcription is a multistep process requiring release of promoter-proximal paused RNA polymerase II (Pol2) by the histone acetylation reader BRD4 and the Pol2 kinase CDK9. Here, we show that recruitment of co-regulators including Mediator and Cohesin by β-catenin changes the mode of transcriptional regulation at BRD4/CDK9-bound loci in 2iL. This switch renders pluripotency genes more reliant on transcriptional initiation and less on Pol2 pause release for effective gene body elongation. Conversely, cell cycle genes are not bound by β-catenin and are still dependent on Pol2 pause release. Thus, pluripotency is more resistant to BRD4/CDK9 suppression in 2iL while self-renewal remains highly sensitive. Our findings help to explain how pluripotency is shielded in the ground state and provide insight into transcriptional adaptation upon network perturbation in other contexts.

2020-07-01 | GSE123691 | GEO

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [ATAC-seq]

2020-07-01 | GSE123690 | GEO

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus

Project description:β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus

| PRJNA509601 | ENA

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [RNA-seq]

Project description:β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [RNA-seq]

| PRJNA509604 | ENA

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [ATAC-seq]

Project description:β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [ATAC-seq]

| PRJNA509605 | ENA

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [GRO-seq]

Project description:β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [GRO-seq]

| PRJNA589310 | ENA

The transcriptional and epigenomic foundations of ground state pluripotency.

Project description:Mouse embryonic stem (ES) cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two kinases (Mek and GSK3), a condition known as "2i" postulated to establish a naive ground state. We show that the transcriptome and epigenome profiles of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes, reduced prevalence at promoters of the repressive histone modification H3K27me3, and fewer bivalent domains, which are thought to mark genes poised for either up- or downregulation. Nonetheless, serum- and 2i-grown ES cells have similar differentiation potential. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. These findings suggest that transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate or multilineage priming.

| S-EPMC3398752 | biostudies-literature

Proteome Analysis of Ground State Pluripotency.

Project description:The differentiation potential of pluripotent embryonic stem cells (ESCs) can be manipulated via serum and medium conditions for direct cellular development or to maintain a naïve ground state. The self-renewal state of ESCs can thus be induced by adding inhibitors of mitogen activated protein kinase (MAPK) and glycogen synthase kinase-3 (Gsk3), known as 2 inhibitors (2i) treatment. We have used a shotgun proteomics approach to investigate differences in protein expressions between 2i- and serum-grown mESCs. The results indicated that 164 proteins were significantly upregulated and 107 proteins downregulated in 2i-grown cells compared to serum. Protein pathways in 2i-grown cells with the highest enrichment were associated with glycolysis and gluconeogenesis. Protein pathways related to organ development were downregulated in 2i-grown cells. In serum-grown ESCs, protein pathways involved in integrin and focal adhesion, and signaling proteins involved in the actin cytoskeleton regulation were enriched. We observed a number of nuclear proteins which were mostly involved in self-renewal maintenance and were expressed at higher levels in 2i compared to serum - Dnmt1, Map2k1, Parp1, Xpo4, Eif3g, Smarca4/Brg1 and Smarcc1/Baf155. Collectively, the results provided an insight into the key protein pathways used by ESCs in the ground state or metastable conditions through 2i or serum culture medium, respectively.

| S-EPMC4680864 | biostudies-other

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