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Polyamine metabolism regulates the T cell epigenome through hypusination [ATAC-seq]

ABSTRACT: Polyamine metabolism regulates the T cell epigenome through hypusination [ATAC-seq]

PROVIDER: PRJNA662099 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12604740_1.fastq.gz	Fastqsanger.gz
	SRR12604740_2.fastq.gz	Fastqsanger.gz
	SRR12604741_1.fastq.gz	Fastqsanger.gz
	SRR12604741_2.fastq.gz	Fastqsanger.gz
	SRR12604742_1.fastq.gz	Fastqsanger.gz

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Polyamine metabolism regulates the T cell epigenome through hypusination

Project description:Polyamine metabolism regulates the T cell epigenome through hypusination

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Polyamine metabolism regulates the T cell epigenome through hypusination [RNA-seq]

Project description:Polyamine metabolism regulates the T cell epigenome through hypusination [RNA-seq]

| PRJNA662098 | ENA

Polyamine metabolism regulates the T cell epigenome through hypusination [ATAC-seq]

Project description:We report here a central role for polyamines in T cell differentiation and function. Deficiency in ornithine decarboxylase (ODC), a critical enzyme for polyamine synthesis, resulted in a profound failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage- defining transcription factors across TH1, TH2, TH17, and Treg polarizing conditions, and enhanced colitogenic potential. T cells deficient in deoxyhypusine synthase (DHPS) or deoxyhypusine hydroxylase (DOHH), which sequentially utilize polyamines to generate hypusine, phenocopied Odc-deficient T cells, and mice in which T cells lacked Dhps or Dohh developed colitis. Polyamine-hypusine pathway enzyme deficiency caused widespread chromatin and transcriptional dysregulation accompanied by alterations in histone methylation, histone acetylation, and TCA cycle metabolites. Epigenetic modulation by 2-hydroxyglutarate, or histone acetyltransferase inhibition, restored CD4+ T cell subset specification. Thus, polyamine synthesis via hypusine is critical for maintaining the epigenome to focus TH cell subset fidelity.

2021-07-07 | GSE157597 | GEO

YAP/TAZ drives cell proliferation and tumour growth via a polyamine-eIF5A hypusination-LSD1 axis

Project description:Here using mouse genetic models and human cancer cells, we show that YAP/TAZ reprogram polyamine metabolism to promote cell proliferation and tumor growth. Mechanistically, YAP/TAZ increases polyamine synthesis mainly through direct upregulation of the major rate-limiting enzyme ornithine decarboxylase 1. We further demonstrate that the polyamine spermidine sustains eukaryotic translation factor 5A (eIF5A) hypusination to support efficient translation of histone demethylase LSD1 that maintains a favored epigenetic status for YAP/TAZ-induced cell proliferation. Furthermore, inhibiting either polyamine synthesis or LSD1 can suppress YAP/TAZ-induced cell proliferation in mouse liver and human cancer cells. Thus our study identifies a YAP/TAZ-polyamine-eIF5A hypusination-LSD1 axis as required for YAP/TAZ-induced cell proliferation and tumor growth and suggests LSD1 as a critical target of polyamine in tumorigenesis.

2022-01-01 | GSE174041 | GEO

Polyamine metabolism regulates the T cell epigenome through hypusination [RNA-seq]

2021-07-07 | GSE157596 | GEO

YAP/TAZ drives cell proliferation and tumour growth via a polyamine-eIF5A hypusination-LSD1 axis (RNA-Seq)

2022-01-01 | GSE176329 | GEO

Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma

Project description:BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance greatly compromises their therapeutic efficacy. Here, we elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reverses vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Finally, inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro and in vivo in a xenograft model. With the polyamine biosynthesis signature correlated with poor prognosis in BRAF mutant melanoma patients, our findings reveal that the polyamine-hypusination-mitochondrial respiration pathway is an effective therapeutic target that can maximize the therapeutic efficacy of existing BRAF inhibitors.

2024-07-10 | GSE243344 | GEO

Chemical genetic interaction linking eIF5A hypusination and mitochondrial integrity

Project description:The eukaryotic translation factor eIF5A plays an important role in translation elongation, especially across stretches of prolines and charged amino acids, and in translation termination. eIF5A undergoes hypusination, a post-translational modification unique to this protein, although the role of hypusination in the function of eIF5A remains elusive. Here, we investigated the cellular defects induced by the hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane). Proteome, translatome, and transcriptome analyses indicated that GC7 downregulated a subset of mitochondrial proteins and DNA, causing mitochondrial stress and eliciting the integrated stress response. Chemical genomic screening using barcoded shRNA libraries identified genes encoding proteins involved in polyamine metabolism/transport and MPV17L2, a mitochondrial disease gene homologue whose product regulates mitochondrial translation. Depletion of MPV17L2 caused hypersensitivity to GC7 and phenocopied the effects of GC7 treatment. These results suggest that eIF5A hypusination and MPV17L2 synthetically regulate mitochondrial molecular synthesis and integrity.

2025-05-06 | GSE266331 | GEO

P53 dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance

Project description:Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we found that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identified eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identified a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism and senescence immune surveillance.

2025-04-24 | GSE272725 | GEO

Polyamine metabolism regulates the T cell epigenome through hypusination

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-07 | GSE157598 | GEO