Rate Limiting Enzymes in Nucleotide Metabolism Synchronize Nucleotide Biosynthesis and Chromatin Formation [ATAC-Seq]
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PROVIDER: PRJNA1327867 | ENA |
REPOSITORIES: ENA
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Project description:Rate Limiting Enzymes in Nucleotide Metabolism Synchronize Nucleotide Biosynthesis and Chromatin Formation [RNA-Seq]
| PRJNA1327860 | ENA
Project description:Fundamental cellular processes including replication, transcription, and repair rely on both an adequate nucleotide supply and sufficient availability of new histones. Chromatin disassembly and reassembly is crucial to maintain genome stability, and is regulated by the orderly engagement of histones with a series of histone chaperones that guide newly synthesized histones from ribosomes to DNA. Although the synthesis of nucleotides and the histone proteins are the two major biosynthetic processes to complete the formation of chromatin, our knowledge about the coordination of these processes is limited. Phosphoribosyl pyrophosphate synthetases (PRPSs) catalyze the rate-limiting step in the nucleotide biosynthesis pathway. PRPS enzymes form a complex with PRPS-associated proteins (PRPSAPs). In the present study, we discover that PRPS-PRPSAP enzyme complex are part of the histone chaperone network involving HSP70/90, NASP, HAT1/RBBP7 and importin-4 to regulate chromatin assembly. We show PRPS enzymes are essential not only for nucleotide biogenesis, but together with PRPSAP also play a key role in the heterodimerization of H3-H4 and posttranslational modification of nascent histones, early steps in the process of histone maturation. Depletion of PRPS proteins leads to limited histone availability and therefore to impaired chromatin assembly. Our discovery bridges nucleotide metabolism and chromatin regulation and provides first evidence on how nucleotide biogenesis and chromatin dynamics work in synchrony.
2025-09-16 | GSE307948 | GEO
Project description:Fundamental cellular processes including replication, transcription, and repair rely on both an adequate nucleotide supply and sufficient availability of new histones. Chromatin disassembly and reassembly is crucial to maintain genome stability, and is regulated by the orderly engagement of histones with a series of histone chaperones that guide newly synthesized histones from ribosomes to DNA. Although the synthesis of nucleotides and the histone proteins are the two major biosynthetic processes to complete the formation of chromatin, our knowledge about the coordination of these processes is limited. Phosphoribosyl pyrophosphate synthetases (PRPSs) catalyze the rate-limiting step in the nucleotide biosynthesis pathway. PRPS enzymes form a complex with PRPS-associated proteins (PRPSAPs). In the present study, we discover that PRPS-PRPSAP enzyme complex are part of the histone chaperone network involving HSP70/90, NASP, HAT1/RBBP7 and importin-4 to regulate chromatin assembly. We show PRPS enzymes are essential not only for nucleotide biogenesis, but together with PRPSAP also play a key role in the heterodimerization of H3-H4 and posttranslational modification of nascent histones, early steps in the process of histone maturation. Depletion of PRPS proteins leads to limited histone availability and therefore to impaired chromatin assembly. Our discovery bridges nucleotide metabolism and chromatin regulation and provides first evidence on how nucleotide biogenesis and chromatin dynamics work in synchrony.
2025-09-16 | GSE307947 | GEO
Project description:In summary, we discovered (1) that glucose dose-dependently inhibits cardiac maturation in vitro and in vivo, (2) that the maturation-inhibitory effect is dependent on nucleotide biosynthesis via the PPP, (3) that the developing heart accomplishes glucose deprivation condition by limiting the glucose uptake at late gestational stages during normal embryogenesis, and (4) that perturbation of the glucose deprivation in gestational diabetes affects natural cardiomyocyte maturation and potentially contributes to congenital heart disease.
2017-12-01 | GSE84814 | GEO
Project description:Mitochondrial reorganization is rate-limiting for direct cardiac reprogramming
| PRJNA1120770 | ENA
Project description:A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARg and C/EBPa. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondria were the most altered transcriptional signature in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARg. Moreover, inhibition of FAO restored PPARg expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.
2024-04-29 | GSE265830 | GEO
Project description:The translational efficiency of mRNAs in cells progressing synchronously through the mitotic cell cycle and having to meet their growth requirements for cell division has not been interrogated. Here, we used ribosome profiling of a cell-size series from the time of cell birth, to identify for the first time yeast mRNAs under periodic translational control. Late in the cell cycle, there was coordinate translational activation of mRNAs encoding lipid biosynthesis enzymes. An upstream open reading frame (uORF) mediates the translational control of ACC1, the mRNA encoding the rate-limiting enzyme acetyl-CoA carboxylase. The ACC1 uORF also adjusts Acc1p protein levels in different nutrients. Mutating the ACC1 uORF delayed cell cycle progression, reduced cell size and suppressed the replicative longevity of cells lacking the Sch9p protein kinase, the yeast S6 kinase ortholog. These findings reveal unexpected links between lipogenesis and protein synthesis in mitotic cell divisions
2017-01-09 | GSE81932 | GEO
Project description:Identification of BBX proteins as rate-limiting co-factors of HY5
| PRJNA564640 | ENA
Project description:Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied mass-spectrometry based quantitative proteomics on isolated mitochondria from mice sacrificed throughout the day and identified extensive oscillations in the mitochondrial proteome. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or upon nutritional challenge such as high fat diet. We propose that the clock proteins PER1/2 optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby serve as a rheostat for mitochondrial nutrient utilization.
2018-10-17 | PXD001732 | Pride
Project description:In Trypanosoma brucei, there are fourteen enzymatic biotransformations that collectively convert glucose into five essential nucleotide sugars: UDP-Glc, UDP-Gal, UDP-GlcNAc, GDP-Man and GDP-Fuc. These biotransformations are catalyzed by thirteen discrete enzymes, five of which possess putative peroxisome targeting sequences. Published experimental analyses using immunofluorescence microscopy and/or digitonin latency and/or subcellular fractionation and/or organelle proteomics have localized eight and six of these enzymes to the glycosomes of bloodstream form and procyclic form T. brucei, respectively. Here we increase these glycosome localizations to eleven in both lifecycle stages while noting that one, phospho-N-acetylglucosamine mutase, also localizes to the cytoplasm. In the course of these studies, the heterogeneity of glycosome contents was also noted. These data suggest that, unlike other eukaryotes, all of nucleotide sugar biosynthesis in T. brucei is compartmentalized to the glycosomes in both lifecycle stages.
2021-01-28 | PXD023124 | Pride