Polyamine metabolism regulates the T cell epigenome through hypusination
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PROVIDER: PRJNA662095 | ENA |
REPOSITORIES: ENA
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Project description:Polyamine metabolism regulates the T cell epigenome through hypusination [ATAC-seq]
| PRJNA662099 | ENA
Project description:Polyamine metabolism regulates the T cell epigenome through hypusination [RNA-seq]
| PRJNA662098 | ENA
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
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 | GSE157596 | GEO
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
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 | GSE176329 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-07-07 | GSE157598 | GEO
Project description:Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors by inhibition of deoxyhypusine synthase abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.
2023-01-25 | MSV000091139 | MassIVE
Project description:The eukaryotic translation factor eIF5A plays an essential role in translation elongation, especially across stretches of prolines and charged amino acids, and in translation termination. Although eIF5A is subjected to hypusination, a post-translational modification unique to this protein, how hypusination contributes to the eIF5A function remains elusive. Here we investigated the cellular defects induced by hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane). Through proteome, translatome and transcriptome analysis, we found that GC7 decreased a subset of mitochondrial proteins and DNA (mtDNA). Furthermore, chemical genomic screening using barcoded shRNA libraries identified genes for particular proteins involved in polyamine metabolism and a mitochondrial protein MPV17L2 as those altering the cytotoxicity induced by GC7. Depletion of MPV17L2 led to hypersensitivity to GC7 as well as the decreases in mitochondrial proteins and mtDNA. Moreover, metabolome analysis revealed that MPV17L2 depletion and GC7 treatment additively decreased the amount of proline and asparagine. Our results indicate that MPV17L2 displays a synthetic lethal interaction with the eIF5A hypusination targeted by GC7. The eukaryotic translation factor eIF5A plays an essential role in translation elongation, especially across stretches of prolines and charged amino acids, and in translation termination. Although eIF5A is subjected to hypusination, a post-translational modification unique to this protein, how hypusination contributes to the eIF5A function remains elusive. Here we investigated the cellular defects induced by hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane). Through proteome, translatome and transcriptome analysis, we found that GC7 decreased a subset of mitochondrial proteins and DNA (mtDNA). Furthermore, chemical genomic screening using barcoded shRNA libraries identified genes for particular proteins involved in polyamine metabolism and a mitochondrial protein MPV17L2 as those altering the cytotoxicity induced by GC7. Depletion of MPV17L2 led to hypersensitivity to GC7 as well as the decreases in mitochondrial proteins and mtDNA. Moreover, metabolome analysis revealed that MPV17L2 depletion and GC7 treatment additively decreased the amount of proline and asparagine. Our results indicate that MPV17L2 displays a synthetic lethal interaction with the eIF5A hypusination targeted by GC7. numerous molecules serving as valuable therapeutics. The marine natural product girolline has been described as an inhibitor of protein synthesis. Here, we demonstrate that it is not a general translation inhibitor but represents a sequence-specific modulator of translation factor eIF5A. Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling, primarily on AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in ribosome-associated quality control (RQC) and is important in maintaining the efficiency of translational progress. Girolline, therefore, provides a potent tool compound for understanding the interplay between protein production and quality control in a physiological setting and offers a new and selective means of modulating gene expression. numerous molecules serving as valuable therapeutics. The marine natural product girolline has27 been described as an inhibitor of protein synthesis. Here, we demonstrate that it is not a general28 translation inhibitor but represents a sequence-specific modulator of translation factor eIF5A.29 Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling, primarily on30 AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in31 ribosome-associated quality control (RQC) and is important in maintaining the efficiency of32 translational progress. Girolline, therefore, provides a potent tool compound for understanding33 the interplay between protein production and quality control in a physiological setting and offers34 a new and selective means of modulating gene expression.
2024-03-31 | GSE244063 | GEO
Project description:Polyamine metabolism in the human placenta
| PRJEB45391 | ENA