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The effect of the modulation of L2-hydroxyglutarate content in pachytene-diplotene cells of male mice

ABSTRACT: We found that testis of male mice contain high concentrations of L2-hydroxyglutarate (L2HG) specifically in germ cells at pachytene/ diplotene (PD) stage of spermatogenesis. In order to elucidate the function of 2HG we decreased its level by incubating PD cells with 24 mM oxamate and to rescue the putative phenotype by incubation with 24 mM oxamate together with 0.3 mM cell permeable L2HG.

ORGANISM(S): Mus musculus

PROVIDER: GSE169015 | GEO | 2024/03/25

REPOSITORIES: GEO

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The effect of 2HG level on transcriptome at different stages of male mouse meiosis

Project description:We found that L2-hydroxyglutarate (2HG) level is 15 times higher in pachytene-diplotene (PD) stage as compared to leptotene-zygotene (LZ) stage. Since 2HG shows epigenetic effects we asked if the addition of 2HG to LZ cells or the decrease of 2HG level in PD cells will cause changes in gene expression.

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The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

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The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

Project description:Study aim: Investigate the effect of S-2HG (2-hydroxyglutarate) metabolite on the mRNA levels of human CD8 T cells Methods: Naïve CD8 T cells were isolated from human healthy donors. The CD8 T cells were aCD3/CD28 beads (1:1 bead-to-cell ratio) and IL-2 (30 U/ml) for 4 days. The cells were treated with S-2HG (0.4 mM) or vehicle (H2O) from the day of isolation and for 12 days before collection. Library preparation and paired-end RNA sequencing using Illumina NextSeq 500, as well as downstream data analysis, were performed by Active Motif.

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D- 2-hydroxyglutarate is an immunometabolite that accumulates in macrophages after TLR activation and inhibits inflammatory responses

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(R)-2-hydroxyglutarate inhibits KDM5 histone lysine demethylases to drive tumorigenesis in IDH-mutant cancers

Project description:Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemias (AMLs) and gliomas1-3. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG]4,5, an oncometabolite that induces cellular transformation by dysregulating 2OG-dependent enzymes. The only direct target of (R)-2HG known to contribute to transformation is the 5-methylcytosine hydroxylase TET2, and there is ample evidence to suggest that (R)-2HG drives leukemogenesis at least in part by inhibiting TET26,7. However, IDH mutations, but not TET2 mutations, are specifically associated with aggressive hematologic diseases, suggesting that (R)-2HG has targets other than TET2 that contribute to mutant IDH-mediated transformation. Here, we report that (R)-2HG directly inhibits KDM5 histone lysine demethylases in IDH-mutant AMLs and gliomas to induce cellular transformation. These studies provide a functional link between dysregulation of histone lysine methylation and tumorigenesis in IDH-mutant cancers.

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Project description:Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-Hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2- hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D2-HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span—recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant upregulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition. We have performed microarray expression profiling of hearts from IDH2 mutant and control mice.

2014-03-01 | E-GEOD-54838 | biostudies-arrayexpress

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