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Transcriptional responses to GSK3 inhibitor and MEK inhibitor on 2i-adapted mouse embryonic stem cells

ABSTRACT: The objective of this study was to investigate the roles of GSK3 inhibitor CHIR99021 and MEK inhibitor PD0325901 on 2i-adapted mouse embryonic stem cells (ESCs) in serum-free conditions.Canonical Wnt signaling supports the pluripotency of mouse ESCs but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of mouse ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in mouse ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest that Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for mouse ESC culture suggests that MEK/ERK signaling and canonical Wnt signaling combine to mouse promote ESC differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE43421 | GEO | 2013/03/01

SECONDARY ACCESSION(S): PRJNA186781

REPOSITORIES: GEO

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Transcriptional responses to GSK3 inhibitor and MEK inhibitor on 2i-adapted mouse embryonic stem cells

Project description:The objective of this study was to investigate the roles of GSK3 inhibitor CHIR99021 and MEK inhibitor PD0325901 on 2i-adapted mouse embryonic stem cells (ESCs) in serum-free conditions.Canonical Wnt signaling supports the pluripotency of mouse ESCs but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of mouse ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in mouse ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest that Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for mouse ESC culture suggests that MEK/ERK signaling and canonical Wnt signaling combine to mouse promote ESC differentiation. Triplicates of mouse embryonic stem cells cultured under the following conditions: 1) CHIR99021+PD0325901+LIF; 2) CHIR99021+PD0325901; 3) CHIR99021; 4) PD0325901; 5) DMSO

2013-03-01 | E-GEOD-43421 | biostudies-arrayexpress

ChIP-seq analysis of β-catenin in mouse embryonic stem cells treated with GSK3 inhibitor CHIR99021 under serum+LIF standard condition.

Project description:The objective of this study was to identify the direct target genes of β-catenin acting downstream of canonical Wnt signaling in mouse embryonic stem cells (ESCs).Canonical Wnt signaling supports the pluripotency of mouse ESCs but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of mouse ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in mouse ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest that Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for mouse ESC culture suggests that MEK/ERK signaling and canonical Wnt signaling combine to promote mouse ESC differentiation.

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Transcriptional responses to Wnt pathway stimulation in mouse embryonic stem cells cultured in serum+LIF condition

Project description:The objective of this study was to identify genes regulated by canonical Wnt signaling in mouse embryonic stem cells (ESCs).Canonical Wnt signaling supports the pluripotency of mouse ESCs but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of mouse ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in mouse ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest that Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for mouse ESC culture suggests that MEK/ERK signaling and canonical Wnt signaling combine to promote mouse ESC differentiation.

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Transcriptional responses to Wnt pathway stimulation in mouse embryonic stem cells cultured in serum+LIF condition

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2013-03-01 | E-GEOD-43420 | biostudies-arrayexpress

ChIP-seq analysis of M-NM-2-catenin in mouse embryonic stem cells treated with GSK3 inhibitor CHIR99021 under serum+LIF standard condition.

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2013-03-01 | E-GEOD-43565 | biostudies-arrayexpress

Wnt and Tcf3-mediated regulation of gene expression in mouse embryonic stem cells

Project description:The observation that Tcf3 (MGI name: Tcf7l1) bound the same genes as core stem cell transcription factors, Oct4 (MGI name:Pou5f1), Sox2 and Nanog, revealed a potentially important aspect of the poorly understood mechanism whereby Wnts stimulate self renewal of pluripotent mouse embryonic stem (ES) cells. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signaling suggested Tcf3 should activate target genes in response to Wnts, here we show that Wnt3a and Tcf3 effectively antagonize each other’s effects on gene expression. Genetic ablation of Tcf3 caused similar effects as treating cells with recombinant Wnt3a. Moreover, Tcf3 was not necessary for Wnt3a-stimulation of gene expression as the majority of Wnt3a-stimulated genes exhibited a greater increase in Tcf3-/- ES cells than in Tcf3+/+ ES cells. These expression data, together with genetic experiments, show that Wnt3a stimulates ES cell self renewal by inhibiting Tcf3. Tcf3+/+ and Tcf3-/- mouse embryonic stem cells were cultured in self renewal conditions containing recombinant Wnt3a for RNA extraction and hybridization on Affymetrix microarrays.

2011-02-24 | E-GEOD-27455 | biostudies-arrayexpress

Wnt and Tcf3-mediated regulation of gene expression in mouse embryonic stem cells

2011-02-24 | GSE27455 | GEO

Selective influence of Sox2 on POU transcription factor binding in embryonic and neural stem cells

Project description:Embryonic stem cell (ESCs) identity is orchestrated by co-operativity between the transcription factors (TFs) Sox2 and the class V POU-TF, Oct4 at composite Sox/Oct motifs. Neural stem cells (NSCs) lack Oct4 but express Sox2 and class III POU-TFs. This raises the question of how Sox2 interacts with POU-TFs to transcriptionally specify ESCs or NSCs. Here we show that Oct4 alone binds the Sox/Oct motif and the octamer-containing palindromic MORE equally well. Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to the MORE, and is unaffected by Sox2. ChIP-seq in NSCs shows the MORE to be the most enriched motif for class III POU-TFs, with MORE sub-types apparent, but no Sox/Oct motif enrichment. These results suggest that in NSCs, co-operativity between Sox2 and class III POU-TFs may not occur and that POU-TF driven transcription uses predominantly the MORE cis architecture. Thus, distinct interactions between Sox2 and POU-TF subclasses distinguish pluripotent ESCs from multipotent NSCs, providing molecular insight into how Oct4 alone can convert NSCs to pluripotency.

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2020-12-22 | GSE154607 | GEO

β-catenin associated protein complex maintains ground state mouse embryonic stem cell by regulating lineage development

Project description:Mouse embryonic stem (ES) cells cultured in defined medium with MEK and GSK3 inhibitors (2i) resemble the pre-implantation epiblast in the ground state, with full development capacity including the somatic lineages and the germline. Although β-catenin is known to be crucial for naive pluripotency of ES cells, the mechanism is not fully understood. Here we showed that β-catenin interacted with a repressive protein complex to maintain the ground state of ES cells by fine-tuning their lineage development potential. Absence of β-catenin impaired ES cell self-renewal without affecting the core self-renewal circuitry of Oct4, Sox2 and Nanog as well as other pluripotency factors. However, β-catenin-deficient cells showed a primed state transcriptional signature with perturbed expression of germline and neuronal lineage genes. Knockdown of Tcf7l1, the repressor in canonical Wnt signaling pathway, did not completely rescue the β-catenin-deficient phenotype of ES cells. Mechanistically, β-catenin formed a novel biochemical complex with E2F6, HP1γ and HMGA2 to restrain ES cells from differentiation by co-occupying the promoters of germline and neuronal lineage regulators independent of TCF7L1. Overall, out work showed that β-catenin maintained ground state ES cells by orchestrating their development plasticity through a repressive protein complex with E2F6, HP1γ and HMGA2.

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