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α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE247634 | GEO | 2025/02/27

REPOSITORIES: GEO

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α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [RNA-Seq]

Project description:Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.

2025-02-27 | GSE247631 | GEO

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [ATAC-Seq]

2025-02-27 | GSE247630 | GEO

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [scRNA-Seq 2D]

2025-02-27 | GSE247633 | GEO

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [scRNA-Seq 3D]

2025-02-27 | GSE270957 | GEO

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells

Project description:α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells

| PRJNA1039841 | ENA

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [ATAC-Seq]

Project description:α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [ATAC-Seq]

| PRJNA1039843 | ENA

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [RNA-Seq]

Project description:α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [RNA-Seq]

| PRJNA1039845 | ENA

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [scRNA-Seq 3D]

Project description:α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [scRNA-Seq 3D]

| PRJNA1129112 | ENA

α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [scRNA-Seq 2D]

Project description:α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells [scRNA-Seq 2D]

| PRJNA1039846 | ENA

Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells.

Project description:The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.

| S-EPMC4336218 | biostudies-literature

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