Early methionine availability attenuates T cell exhaustion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA913938 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR22753641_1.fastq.gz | Fastqsanger.gz | |||
| SRR22753641_2.fastq.gz | Fastqsanger.gz | |||
| SRR22753644_1.fastq.gz | Fastqsanger.gz | |||
| SRR22753644_2.fastq.gz | Fastqsanger.gz |
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Project description:T cell receptor (TCR) activation is regulated in multifaceted ways, including niche-specific nutrient availability. We investigated how methionine (Met) availability and TCR signaling interplay in the earliest events of T cell activation to affect subsequent cell fate. Limiting Met during the initial 30 minutes of TCR engagement increased Ca2+ influx, NFAT1 (Nfatc2) activation and promoter occupancy leading to T cell exhaustion. We identified changes in the protein arginine methylome during the initial TCR engagement and discovered a novel arginine methylation of a Ca2+-activated potassium transporter, KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in murine tumour and infection models. Furthermore, acute Met supplementation at early stages reduced nuclear NFAT1 in tumour-infiltrating T cells and augmented their anti-tumour activity. Our findings identify a metabolic event occurring early after T cell activation that influences cell fate.
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Project description:Cancer cells exhibit a well-documented, yet poorly understood, dependence on exogenous methionine, despite retaining the capacity to convert homocysteine to methionine. In contrast, non-tumorigenic cells can proliferate when methionine is replaced by homocysteine. To investigate the mechanistic basis of this methionine dependence, we examined how methionine metabolism impacts cell cycle progression. We identified carboxy-methylation of the catalytic subunit of Protein Phosphatase 2A (PP2A) as a critical node linking methionine availability to proliferation. PP2A methylation was found to be highly sensitive to intracellular S-adenosylmethionine (SAM) levels, with reduced methylation correlating with impaired proliferation under methionine restriction. Overexpression of Protein Phosphatase Methylesterase-1 (PME-1), which demethylates PP2A, or expression of a Leu309-deleted PP2A mutant that mimics the demethylated form, was sufficient to reduce proliferation even in methionine-independent cells. These findings support a model in which methionine limitation lowers SAM availability, thereby decreasing PP2A methylation and impairing cell cycle progression. Our study reveals a novel mechanistic link between methionine metabolism and the cell cycle and suggests that PP2A methylation plays a key role in the unique methionine dependence of cancer cells.
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Project description:Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2, which senses methionine levels. Additionally, methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
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Project description:Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2, which senses methionine levels. Additionally, methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
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Project description:Methionine availability influences essential H3K36me3 dynamics during cell differentiation
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Project description:Methionine availability influences essential H3K36me3 dynamics during cell differentiation [ChIP-seq]
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Project description:Methionine availability influences essential H3K36me3 dynamics during cell differentiation [ATAC-seq]
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Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent versus methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generic rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, the methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but trigger different outcomesin methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and tight junctions in the cellular response to methionine stress in melanoma.
2023-05-03 | GSE225944 | GEO
Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent versus methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generic rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, the methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but trigger different outcomesin methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and tight junctions in the cellular response to methionine stress in melanoma.
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