The genome-wide targeting of H3K18la in H1299 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE207814 | GEO | 2023/07/30
REPOSITORIES: GEO
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Project description:Histone lactylation has been served as a novel epigenetic modification that directly stimulates gene transcription from chromatin. In order to study the regulatory mechanisms of H3K18la in non-small cell lung cancer (NSCLC), we performed ChIP-Seq to identify its target genes in NCI-H1299 cell lines.
2024-08-06 | GSE245990 | 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:The genome-wide targeting of H3K18la in H1299 cells
| PRJNA857271 | ENA
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 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: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:Tumor cells are known for excessive lactate production, due to Warburg effect, and transcriptional dysregulation. However, how lactate influences the epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cell remains unclear. Addressing this gap, we analyzed genome-wide modification of H3K18 lactylation (H3K18la) in T-cell acute lymphoblastic leukemia (T-ALL). Integrated analysis with histone modifications with established functions show the H3K18la is mainly involved in active regulation of gene transcription. We report increased lactate and H3K18la modification levels in T-ALL as compared to normal T cells. We observe clusters of H3K18la modifications in patterns reminiscent of super-enhancers. We show a notable shift of genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, correlating with altered gene transcription profiles. By disrupting H3K18la modification, we uncover both synergetic and divergent changes between H3K18la and H3K27ac modifications, suggesting the H3K18la and H3K27ac modifications may have specific regulation mechanisms correspondingly. These findings expand our understanding of metabolic disruptions involvement in transcription dysregulation through epigenetic changes in T-ALL, and emphasize the collective importance of histone modifications in maintaining oncogenic epigenetic stability.
2024-05-31 | GSE263584 | GEO
Project description:Tumor cells are known for excessive lactate production, due to Warburg effect, and transcriptional dysregulation. However, how lactate influences the epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cell remains unclear. Addressing this gap, we analyzed genome-wide modification of H3K18 lactylation (H3K18la) in T-cell acute lymphoblastic leukemia (T-ALL). Integrated analysis with histone modifications with established functions show the H3K18la is mainly involved in active regulation of gene transcription. We report increased lactate and H3K18la modification levels in T-ALL as compared to normal T cells. We observe clusters of H3K18la modifications in patterns reminiscent of super-enhancers. We show a notable shift of genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, correlating with altered gene transcription profiles. By disrupting H3K18la modification, we uncover both synergetic and divergent changes between H3K18la and H3K27ac modifications, suggesting the H3K18la and H3K27ac modifications may have specific regulation mechanisms correspondingly. These findings expand our understanding of metabolic disruptions involvement in transcription dysregulation through epigenetic changes in T-ALL, and emphasize the collective importance of histone modifications in maintaining oncogenic epigenetic stability.
2024-05-20 | GSE263697 | GEO
Project description:We profiled the genome-wide distribution of H3K18la in samples originating from 6 different in vitro and in vivo mouse samples, representing 3 tissues: embryonic stem cells, macrophages and skeletal muscle as well as in human skeletal muscle and compared them to the profiles of other well-established histone modifications as well as gene expression patterns. Globally, we found that H3K18la profiles resemble H3K27ac profiles better than any other investigated hPTM, including H3K4me3, but that they do not copy them. For all samples, H3K18la marked active CGI promoters of highly expressed genes which were remarkably shared across the different mouse tissues and which contained many housekeeping genes. Promoter H3K18la levels correlated positively to both H3K27ac and H3K4me3 levels as well as to gene expression levels. In addition, we found that H3K18la is enriched at tissue-type specific, active enhancers, which are particularly tissue-type-specific, especially when compared to the H3K18la-marked promoter regions. Accordingly, enhancer H3K18la levels correlate positively to the expression of their nearest genes. Additionally, genes closest to enhancers with high H3K18la levels predominantly consist of tissue-type specific marker genes. Overall, we showed that H3K18la is not only a marker for active promoters, but that it also marks active enhancers, and this both in embryonic tissues and differentiated tissues, and both in mouse and in human.
2022-09-14 | GSE195859 | GEO
Project description:Histone lysine lactylation is a physiologically and pathologically 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 lactyl-CoA synthetase in the nucleus 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 and radioresistance of gliomas. The GTPSCS represents the inaugural enzyme that can catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression patterns in glioma.
2024-12-02 | PXD056791 | Pride