A novel, druggable casacade links methionine metabolism to epigenomic reprogramming in squamous cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1020847 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26170100_1.fastq.gz | Fastqsanger.gz | |||
| SRR26170100_2.fastq.gz | Fastqsanger.gz | |||
| SRR26170101_1.fastq.gz | Fastqsanger.gz | |||
| SRR26170101_2.fastq.gz | Fastqsanger.gz | |||
| SRR26170102_1.fastq.gz | Fastqsanger.gz |
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Project description:DNA and histone methylation represents perhaps the most significant form of epigenetic regulation in mammalian cells, and their deregulation is most notable and pervasive in cancer. Based on our previous study which demonstrated the interplay between cancer metabolism and epigenetic regulation and the public database showing abnormal expression of LAT1 in upper aerodigestive squamous cell carcinoma (UASCC), we aim to investigate the role of LAT1 as a regulator of epigenomic reprogramming in UASCC. To identify the effect of the blockade of LAT1 on epigenetic regulation, we silenced LAT1 in UASCC cell line and performed RNA-Seq. In addition, we confirmed that Knockdown of LAT1 is associated with the downstream genes of EZH2. Therefore, we performed RNA-Seq after silencing EZH2 by transfection of siRNA and Cut&Tag assays using EZH2 and H3K27me3 antibodies
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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: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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Project description:BSA pooling experiment for methionine content in a segrating diploid potato population (CxE). RNA of constrasting individuals for methionine content are pooled together based on their tuber methionine content and marker association with either or both of the identified QTLs for methionine content
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Project description:The genome-wide transcriptional response of S. cerevisiae cells upon transfer to methionine-restricted media is investigated. DHO strain (BY4742 background) was cultivated batch-wise in SDC media at 30C and 180 rpm up to mid-exponential phase (OD600 ~ 0.6). The cells of the main culture were divided in three aliquots at the mid-exponential phase, centrifuged at 6000 rpm for 5 min, washed twice with deionized and distilled sterile water prior to their transfer to the treatment media. Treatment media comprised of SDC + 0.75% methionine for the methionine-restricted case while SDC is used for the control case. Sample collection for transcriptional profiling was done at the 2nd hour of the transfer. The experiments were carried out in biological triplicates.
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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.
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