ArticleStem cell research & therapy2021
AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation.
Article in Stem cell research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 28 citations in OpenAlex.
- Alternate-day fasting enhances leptin sensitivity via JMJD3-dependent epigenetic regulation of the leptin receptor in the hypothalamus.The Journal of nutritional biochemistry · 2026Article
- DNA methylation site loss for plasticity-led novel trait genetic fixation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cadmium exposure induces renal fibrosis by inhibiting hsa_circ_0075684/miR-363-3p/KLF4 signaling pathway.Scientific reports · 2026Article
- The Regulatory Role of mCells · 2026Review
- AKG-TET axis is central to senescence plasticity.iScience · 2026Article
- Review
- Computational assessment of the relationship between metabolism and histone methylation in cancer cells.PloS one · 2026Article
- Proteomic insights into molecular alterations associated with Kawasaki disease in children.Italian journal of pediatrics · 2025Article
- Metabolomics as the missing piece in epigenetics research.Environmental epigenetics · 2025Article
- BRG1 improves reprogramming efficiency by enhancing glycolytic metabolism.Cellular and molecular life sciences : CMLS · 2024Article
- A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation.Reproduction (Cambridge, England) · 2024Article
- Protocol for DNA Methylation Editing of Imprinted Loci and Assessment of the Effects.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Development and evaluation of a novel xeno-free culture medium for human-induced pluripotent stem cells.Stem cell research & therapy · 2022Article
- Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain.Nucleic acids research · 2022Article
- The Role of Ten-Eleven Translocation Proteins in Inflammation.Frontiers in immunology · 2022Review
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
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Abstract
backgroundPhosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival and tumorigenesis. The activation of AKT signaling promotes the cellular reprogramming including generation of induced pluripotent stem cells (iPSCs) and dedifferentiation of primordial germ cells (PGCs). Previous studies suggested that AKT promotes reprogramming by activating proliferation and glycolysis. Here we report a line of evidence that supports the notion that AKT signaling is involved in TET-mediated DNA demethylation during iPSC induction.
methodsAKT signaling was activated in mouse embryonic fibroblasts (MEFs) that were transduced with OCT4, SOX2 and KLF4. Multiomics analyses were conducted in this system to examine the effects of AKT activation on cells undergoing reprogramming.
resultsWe revealed that cells undergoing reprogramming with artificially activated AKT exhibit enhanced anabolic glucose metabolism and accordingly increased level of cytosolic α-ketoglutarate (αKG), which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET is upregulated. Consistent with the upregulation of αKG production and TET, we observed a genome-wide increase in 5-hydroxymethylcytosine (5hmC), which is an intermediate in DNA demethylation. Moreover, the DNA methylation level of ES-cell super-enhancers of pluripotency-related genes is significantly decreased, leading to the upregulation of associated genes. Finally, the transduction of TET and the administration of cell-permeable αKG to somatic cells synergistically enhance cell reprogramming by Yamanaka factors.
conclusionThese results suggest the possibility that the activation of AKT during somatic cell reprogramming promotes epigenetic reprogramming through the hyperactivation of TET at the transcriptional and catalytic levels.
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