Selective GSK3α Inhibition Promotes Self-Renewal Across Different Stem Cell States [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1253971 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33246633.fastq.gz | Fastqsanger.gz |
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Project description:Selective GSK3α Inhibition Promotes Self-Renewal Across Different Stem Cell States
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Project description:Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) represent the naïve and primed pluripotent states, respectively, each requiring distinct culture conditions. In this study, we show that BRD0705, a selective GSK3α inhibitor, significantly enhances the self-renewal of both ESCs and EpiSCs. When combined with IWR1, BRD0705 sustains long-term maintenance of ESCs in a naïve state and EpiSCs in a primed state, even preserving their unique identities under long-term co-culture. Single-cell RNA sequencing and histone mark profiling confirm that this regimen maintains distinct gene expression and epigenetic signatures corresponding to each pluripotent state. Importantly, unlike pan-GSK3 inhibitors CHIR-99021 (CHIR), BRD0705 acts independently of β-catenin signaling, unveiling a novel mechanism for supporting pluripotency. Finally, BRD0705/IWR1 also supports the maintenance of the formative pluripotent stem cells and neural stem cells. Collectively, we propose that GSK3α inhibition may preserve diverse stem cell states by insulating stem cells from differentiation cues and promoting their intrinsic self-renewal capacity. We believe our findings lay the foundation for universal stem cell culture methods with significant regenerative medicine applications.
2025-06-16 | GSE295265 | GEO
Project description:Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) represent the naïve and primed pluripotent states, respectively, each requiring distinct culture conditions. In this study, we show that BRD0705, a selective GSK3α inhibitor, significantly enhances the self-renewal of both ESCs and EpiSCs. When combined with IWR1, BRD0705 sustains long-term maintenance of ESCs in a naïve state and EpiSCs in a primed state, even preserving their unique identities under long-term co-culture. Single-cell RNA sequencing and histone mark profiling confirm that this regimen maintains distinct gene expression and epigenetic signatures corresponding to each pluripotent state. Importantly, unlike pan-GSK3 inhibitors CHIR-99021 (CHIR), BRD0705 acts independently of β-catenin signaling, unveiling a novel mechanism for supporting pluripotency. Finally, BRD0705/IWR1 also supports the maintenance of the formative pluripotent stem cells and neural stem cells. Collectively, we propose that GSK3α inhibition may preserve diverse stem cell states by insulating stem cells from differentiation cues and promoting their intrinsic self-renewal capacity. We believe our findings lay the foundation for universal stem cell culture methods with significant regenerative medicine applications.
2025-06-16 | GSE295263 | GEO
Project description:Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) represent the naïve and primed pluripotent states, respectively, each requiring distinct culture conditions. In this study, we show that BRD0705, a selective GSK3α inhibitor, significantly enhances the self-renewal of both ESCs and EpiSCs. When combined with IWR1, BRD0705 sustains long-term maintenance of ESCs in a naïve state and EpiSCs in a primed state, even preserving their unique identities under long-term co-culture. Single-cell RNA sequencing and histone mark profiling confirm that this regimen maintains distinct gene expression and epigenetic signatures corresponding to each pluripotent state. Importantly, unlike pan-GSK3 inhibitors CHIR-99021 (CHIR), BRD0705 acts independently of β-catenin signaling, unveiling a novel mechanism for supporting pluripotency. Finally, BRD0705/IWR1 also supports the maintenance of the formative pluripotent stem cells and neural stem cells. Collectively, we propose that GSK3α inhibition may preserve diverse stem cell states by insulating stem cells from differentiation cues and promoting their intrinsic self-renewal capacity. We believe our findings lay the foundation for universal stem cell culture methods with significant regenerative medicine applications.
2025-06-16 | GSE295264 | GEO
Project description:Selective GSK3α Inhibition Promotes Self-Renewal Across Different Stem Cell States [RNA-seq]
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Project description:Selective GSK3α Inhibition Promotes Self-Renewal Across Different Stem Cell States [CUT&Tag]
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Project description:This SuperSeries is composed of the SubSeries listed below.
2025-06-16 | GSE295266 | GEO
Project description:Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia: Genome-wide transcriptional profiles for the GSK3α selective inhibitor BRD0507 and for the GSK3α/β dual inhibitor BRD0320 Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the WNT pathway, remains a therapeutic target of interest in many diseases. While dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class to cancer therapy, particularly for the treatment of acute myeloid leukemia (AML). Knockdown of GSK3α or GSK3β individually does not increase β-catenin in certain cellular subtypes and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, only inadequate chemical tools exist. The design of selective ATP competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity, 100% similarity) in their ATP binding domains. Taking advantage of an Asp133®Glu196 “switch” in their hinge binding domains, we present a rational design strategy towards the discovery of a paralog selective set of GSK3 inhibitors. These first-in-class GSK3α and GSK3β selective inhibitors provided insights into GSK3 targeting in AML where GSK3α has been identified as a therapeutic target using genetic approaches. Our GSK3α selective compound (BRD0705) inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells while no effect is observed on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies validate feasibility of paralog selective GSK3α inhibition offering a promising therapeutic approach in AML.
2019-06-16 | GSE109985 | GEO
Project description:Genome-wide transcriptional profiles for the GSK3α selective inhibitor BRD0507 and for the GSK3α/β dual inhibitor BRD0320
| PRJNA432530 | ENA
Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)
2010-12-22 | E-GEOD-25334 | biostudies-arrayexpress