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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [scRNA-Seq 10x]

ABSTRACT: Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [scRNA-Seq 10x]

PROVIDER: PRJNA824806 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18686008.fastq.gz	Fastqsanger.gz
	SRR18686009.fastq.gz	Fastqsanger.gz
	SRR18686010.fastq.gz	Fastqsanger.gz
	SRR18686011.fastq.gz	Fastqsanger.gz
	SRR18686012.fastq.gz	Fastqsanger.gz

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Similar Datasets

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [scRNA-Seq 10x]

Project description:Blocking pyrimidine de novo synthesis via inhibiting Dihydroorotate dehydrogenase (DHODH) is clinically used to treat autoimmunity and to prevent the growth of rapidly dividing cells including activated T-cells. We identified a previously unrecognized resistance of precursors of memory T-cells to pyrimidine starvation. While the treatment effectively blocks effector T-cells, numbers, function and transcriptional profiles of memory T-cells and their precursors remain completely unaltered. We pinpoint this effect to a narrow time-window in the early T-cell expansion phase, when developing effector, but not memory T-cells are selectively vulnerable to pyrimidine starvation. This stems from a higher proliferative pace of early effector T-cells paired with lower pyrimidine synthesis capacity compared to memory precursors. This differential sensitivity constitutes a novel, drug-targetable checkpoint that efficiently diminishes effector T-cells without harming the memory compartment. We envision that knowledge of this pyrimidine synthesis-based cell fate-determining particularity opens up new means to safely manipulate effector T-cell responses.

2023-01-10 | GSE200488 | GEO

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [SCRB-seq]

2023-01-10 | GSE200359 | GEO

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [bulk RNA-seq]

2023-01-10 | GSE200358 | GEO

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development.

Project description:Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development.

| PRJNA824308 | ENA

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [SCRB-seq]

Project description:Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [SCRB-seq]

| PRJNA824310 | ENA

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [bulk RNA-seq]

Project description:Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development [bulk RNA-seq]

| PRJNA824311 | ENA

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T-cell development.

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

2023-01-10 | GSE200360 | GEO

Targeting Pyrimidine Synthesis Accentuates Molecular Therapy Response in Glioblastoma Stem Cells

Project description:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase) or the critical downstream enzyme, DHODH (dihydroorotate dehydrogenase) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a novel therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

2019-04-09 | GSE129438 | GEO

Enzymatic de novo pyrimidine nucleotide synthesis.

Project description:The use of stable isotope labeling has revolutionized NMR studies of nucleic acids, and there is a need for methods of incorporation of specific isotope labels to facilitate specific NMR experiments and applications. Enzymatic synthesis offers an efficient and flexible means to synthesize nucleoside triphosphates from a variety of commercially available specifically labeled precursors, permitting isotope labeling of RNAs prepared by in vitro transcription. Here, we recapitulate de novo pyrimidine biosynthesis in vitro, using recombinantly expressed enzymes to perform efficient single-pot syntheses of UTP and CTP that bear a variety of stable isotope labeling patterns. Filtered NMR experiments on (13)C, (15)N, (2)H-labeled HIV-2 TAR RNA demonstrate the utility and value of this approach. This flexible enzymatic synthesis will make implementing detailed and informative RNA stable isotope labeling schemes substantially more cost-effective and efficient, providing advanced tools for the study of structure and dynamics of RNA molecules.

| S-EPMC3134529 | biostudies-literature

De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defense

Project description:De novo pyrimidine biosynthesis is achieved by cytosolic enzymes, CAD and UMPS, and mitochondrial DHODH. However, how these enzymes are orchestrated remains enigmatical. Here, we show that cytosolic aspartate-producing GOT1 clusters with CAD and UMPS. This cytosolic cluster then connects with DHODH, which is mediated by the mitochondrial outer membrane channel protein VDAC3. Therefore, these proteins form a multi-enzyme complex, named “pyrimidinosome”, involving AMPK as a regulator. Activated AMPK dissociates from the complex, enhancing pyrimidinosome assembly to up-regulate intermediate orotate synthesis, which promotes DHODH-mediated ferroptosis defense. In contrast, pyrimidinosome-mediated UMP biosynthesis is significantly increased in cells lacking AMPK, so that cancer cells with lower expression of AMPK are more reliant on de novo pyrimidine biosynthesis and more vulnerable to its inhibition in vitro and in vivo. Our findings reveal the role of pyrimidinosome in regulating pyrimidine flux and ferroptosis, and suggest a pharmaceutical strategy of targeting pyrimidinosome in cancer treatment.

2023-03-22 | PXD041017 |

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