PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1095427 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28527813_1.fastq.gz | Fastqsanger.gz | |||
| SRR28527813_2.fastq.gz | Fastqsanger.gz | |||
| SRR28527814_1.fastq.gz | Fastqsanger.gz | |||
| SRR28527814_2.fastq.gz | Fastqsanger.gz | |||
| SRR28527815_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.
2024-11-05 | GSE262995 | GEO
Project description:Embryonic stem cells (ESCs) favor glycolysis over oxidative phosphorylation for energy production, and glycolytic metabolism is critical for pluripotency establishment, maintenance and exit. However, how glycolysis regulates the self-renewal and differentiation of ESCs remains elusive. Here, we demonstrated that protein lactylation, regulated by intracellular lactate, contributes to the self-renewal of ESCs. Next, the lactylome profiles of ESCs with and without a lactate dehydrogenase (Ldh) inhibitor, which suppresses the conversion of pyruvate to lactate, were depicted. It was notable that many lactylated proteins are involved in the self-renewal and differentiation of ESCs. We further showed that Esrrb, an orphan nuclear receptor involved in pluripotency maintenance and extraembryonic endoderm stem cell (XEN) differentiation, is lactylated on K228 and K232. Lactylation of Esrrb enhances its activity in promoting ESC self-renewal in the absence of LIF and XEN differentiation of ESCs, through increasing its binding at target genes. Our studies reveal the importance of protein lactation in the self-renewal and XEN differentiation of ESCs, and the underlying mechanism for glycolytic metabolism regulating cell fate choice.
2024-03-01 | GSE237618 | GEO
Project description:To investigate the binding targets of PTBP1 (PTB) and IGF2BP2 (IMP2) in glioma cells, we carried out an unbiased analysis of transcripts bound by PTBP1 and IGF2BP2 using enhanced crosslinking immunoprecipitation followed by high-throughput sequencing (eCLIP) in A172 glioma cells. We repeated the eCLIP method twice in each experiment, and found that the ratio of PTBP1 and IGF2BP2 binding mRNAs overlap was very high.
2022-01-02 | GSE192792 | GEO
Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a robust lactyl-CoA synthetase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation of glioma cells and facilitates tumor formation in mice. In addition, GTPSCS is upregulated in glioma and correlates with glioma malignancy, while histone H3K18la, and GDF15 levels are positively associated with glioma malignancy and poor prognosis in GBM patients. The GTPSCS-lactyltransferase-histone Kla axis thus represents an epigenetic pathway linking lactate metabolism with an oncogenic gene expression pattern in glioma.
2024-11-26 | GSE248703 | GEO
Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a robust lactyl-CoA synthetase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation of glioma cells and facilitates tumor formation in mice. In addition, GTPSCS is upregulated in glioma and correlates with glioma malignancy, while histone H3K18la, and GDF15 levels are positively associated with glioma malignancy and poor prognosis in GBM patients. The GTPSCS-lactyltransferase-histone Kla axis thus represents an epigenetic pathway linking lactate metabolism with an oncogenic gene expression pattern in glioma.
2024-11-26 | GSE247800 | GEO
Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and hypoxia-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here, we report the identification of GTPSCS as a lactyl-CoA ligase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone H3 lysine 18 lactylation (H3K18la). This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit but also acetylation at the G2 subunit residue K73 (for the interaction between GTPSCS and p300). GTPSCS-p300-mediated histone H3K18la promotes glioma cell proliferation and tumor formation in mice. In addition, histone H3K18la is positively associated with glioma grade and poor prognosis in glioma patients. The LDHA-GTPSCS-lactyltransferase-histone Kla axis thus represents a signal-stimulated epigenetic pathway that mediates the downstream impact of the Warburg effect and hypoxia
2024-12-04 | PXD037672 | Pride
Project description:In order to study the mechanism of histone lactylation, we used glycolysis inhibitors to reduce histone lactylation and applied RNA-seq and ChIP-seq to identify its target genes in ocular melanoma.
2020-08-23 | GSE156674 | GEO
Project description:Cancer-augmented lactogenesis has been described by the Warburg effect, and is associated with several major hallmarks of neoplasia. However, the non-metabolic functions of elevated lactate in physiology and disease remain unknown. Here we report histone lysine lactylation as a new type of epigenetic mechanism and as a functional destination for lactate. Histone lactylation is induced under glycolytic conditions such as hypoxia and M1 macrophage polarization. In the late phase of M1 macrophage polarization, increases in histone lactylation but not acetylation mark M2-like genes for activation. Our findings suggest a feedback mechanism of the innate immune system to switch from proinflammation to resolution through histone Kla-associated gene expression. This mechanism is implemented by the coopted function of lactate and histone lactylation in metabolism and epigenetics. Together, our study opens a new avenue for understanding function of lactate and glycolysis underlined diverse pathophysiological conditions.
2019-08-06 | GSE115354 | GEO
Project description:Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. Many studies have investigated the histone modification mechanisms that regulate cellular senescence and aging. In this study, we show that histone lactylation, an identified histone modification that integrates metabolic processes, epigenetic regulation of gene expression and cellular activities in response to internal and external cues, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways, thereby inhibiting cellular senescence. Furthermore, the modulation of enzymes crucial for histone lactylation, including p300 and HDAC1, leads to reduced histone lactylation and accelerated cellular senescence. Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Running exercise increases the levels of glycolysis and histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways, thereby helping to preserve the proper function of skeletal muscle. Our study highlights the significant roles of histone lactylation in modulating cellular senescence as well as aging-related tissue function, suggesting that this modification may serve as an innovative biomarker for senescence and provides a promising avenue for antiaging intervention via metabolic manipulation.
2024-05-01 | GSE226007 | GEO
Project description:Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. Many studies have investigated the histone modification mechanisms that regulate cellular senescence and aging. In this study, we show that histone lactylation, an identified histone modification that integrates metabolic processes, epigenetic regulation of gene expression and cellular activities in response to internal and external cues, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways, thereby inhibiting cellular senescence. Furthermore, the modulation of enzymes crucial for histone lactylation, including p300 and HDAC1, leads to reduced histone lactylation and accelerated cellular senescence. Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Running exercise increases the levels of glycolysis and histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways, thereby helping to preserve the proper function of skeletal muscle. Our study highlights the significant roles of histone lactylation in modulating cellular senescence as well as aging-related tissue function, suggesting that this modification may serve as an innovative biomarker for senescence and provides a promising avenue for antiaging intervention via metabolic manipulation.
2024-05-01 | GSE226006 | GEO