Nupr1 controls the threshold of quiescent hematopoietic stem cells through p53 signaling pathway
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ABSTRACT:
PROVIDER: PRJNA542594 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9047120_1.fastq.gz | Fastqsanger.gz | |||
| SRR9047120_2.fastq.gz | Fastqsanger.gz | |||
| SRR9047121_1.fastq.gz | Fastqsanger.gz | |||
| SRR9047121_2.fastq.gz | Fastqsanger.gz | |||
| SRR9047122_1.fastq.gz | Fastqsanger.gz |
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Project description:RNAseq were performed to analyze the transcriptomic differences between wild type HSCs and Nupr1-/- HSCs.
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Project description:we uncovered that nuclear protein 1 (Nupr1), a transcription regulatory gene preferentially expressed in HECs, was a negative regulator of EHT. Nupr1 deficiency resulted in plentiful emergence of HSC-competent cells in the AGM region, including HECs and HSPCs. Further single-cell transcriptome combined serial functional assay revealed that loss of Nupr1 prominently accelerate EHT process, also promote the specification of HECs and strengthen their subsequent hematopoietic differentiation potential towards HSPC. Interestingly, we found that numerous inflammatory signals were specifically upregulated in Nupr1-/- EHT relevant populations, as elevated inflammatory response signals have been proved to promote EHT and HSPCs generation.
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Project description:The importance of the p53 protein in the cellular response to DNA damage is well known, but its function during steady-state hematopoiesis has not been established. We have defined a critical role of p53 in regulating hematopoietic stem cell quiescence, especially in promoting the enhanced quiescence seen in HSCs that lack the MEF/ELF4 transcription factor. Transcription profiling of HSCs isolated from wild type and p53 null mice identified Gfi-1 and Necdin as p53 target genes and using lentiviral vectors to upregulate or knockdown the expression of these genes, we show their importance in regulating HSC quiescence. Establishing the role of p53 (and its target genes) in controlling the cell cycle entry of HSCs may lead to therapeutic strategies capable of eliminating quiescent cancer (stem) cells.
2008-11-07 | GSE13448 | GEO
Project description:Nuclear Protein 1 (NUPR1) is a nuclear intrinsically disordered protein of 82 amino acids that plays an important role in stress response and in cancer development. The project was aimed at identifying binding partners of NUPR1 in MiaPaCa-2 cells, in control and after stress condition: glucose starvation during 24h. Lysates from MiaPaCa-2 cells (transfected with NUPR1-Flag or NUPR1-GFP) were used for immunoprecipitation, performed with agarose beads coated with anti-Flag or anti-GFP antibodies. After immunoprecipitation, the eluted proteins were analyzed by LC-MS/MS.
2022-07-29 | PXD035236 | Pride
Project description:The importance of the p53 protein in the cellular response to DNA damage is well known, but its function during steady-state hematopoiesis has not been established. We have defined a critical role of p53 in regulating hematopoietic stem cell quiescence, especially in promoting the enhanced quiescence seen in HSCs that lack the MEF/ELF4 transcription factor. Transcription profiling of HSCs isolated from wild type and p53 null mice identified Gfi-1 and Necdin as p53 target genes and using lentiviral vectors to upregulate or knockdown the expression of these genes, we show their importance in regulating HSC quiescence. Establishing the role of p53 (and its target genes) in controlling the cell cycle entry of HSCs may lead to therapeutic strategies capable of eliminating quiescent cancer (stem) cells. Experiment Overall Design: RNAs isolated from wild type, p53 -/- and p53 -/- Mef -/- LSK cells were used in oligonucleotide arrays (Affymetrix)
2008-11-15 | E-GEOD-13448 | biostudies-arrayexpress
Project description:In response to stress, the p53 tumor suppressor induces arrest or apoptosis by transcriptionally regulating genes that mediate these processes. It has been proposed that the levels of p53 can influence the choice between these different outcomes, but the mechanisms involved are not clear. To gain mechanistic understanding of this p53-dependent cell fate decision, we generated a p53 inducible system that allowed tight regulation of p53 expression in human mammary epithelial cells. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Using microarray and chromatin immunoprecipitation analysis, we showed that low and high levels of p53 bind to and activate the same set of pro arrest and pro apoptotic target genes, induced to lower and higher levels, respectively. We propose that the cell fate decision between arrest and apoptosis in these cells is determined by a higher threshold required for p53 dependent apoptosis. We suggest that high level p53 activation is crucial in order to achieve maximum efficacy of p53 targeted cancer therapies.
2011-07-19 | E-GEOD-30753 | biostudies-arrayexpress
Project description:Expansion of quiescent hematopoietic stem cells in mice
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Project description:Hematopoietic stem cells (HSCs) are maintained in the quiescent state for protection from exhaustion by a number of self-renewal divisions. To understand the in vivo kinetics of quiescent HSCs, we analyzed the cell cycle of CD201+150+48-Lin-Kit+Sca-1+ cells after transplantation and during development and aging using fluorescent ubiquitination-based cell cycle indicator (Fucci) mice to distinguish HSCs at the G0, G1, and S/G2/M phases. The quiescent HSC population, representing a functional HSC pool, rapidly expanded by three weeks after transplantation and by three weeks of age in development and gradually accumulated in bone marrow with aging. Single-cell RNA-sequencing with flow cytometric index sorting suggested that high CD201 and Sca-1 expression levels and a low level of mitochondrial activity were associated with quiescent HSCs. A novel set of candidate quiescent genes in HSCs was also provided. This study implied that controlling quiescent HSCs is important for the in vivo expansion and maintenance of functional HSCs.
2023-02-24 | GSE197439 | GEO
Project description:To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
2018-04-27 | GSE104050 | GEO
Project description:In adults, human hematopoietic stem cells (HSCs) are mostly in a quiescent state (G0 stage) and show multilineage reconstruction. When the cell cycle is activated, HSCs gradually lose the hematopoietic reconstruction ability. It indicates that the maintenance of the quiescent state of HSPCs has very important physiological significance. However, the maintenance and regulation mechanism of the quiescent state of HSCs has not yet been clarified. We found that TSC22D3 was highly enriched in quiescent state HSCs but downregulated in culture with the activation of the cell cycle. We further confirmed that stabilizing TSC22D3 expression in HSCs could promote the maintenance of the quiescent state and provide balanced multilineage reconstitution in primary mouse recipients.We found that overexpression of TSC22D3 can promote the maintenance of the resting state of HSCs and the ability of hematopoietic reconstitution by inhibiting the expression of cell cycle-related kinases. Also we confirmed that TSC22D3 can promote the accumulation of p53 protein in cells and up-regulate the expression of p21, p27 and other proteins by qPCR and western blot. Therefore, we speculate that TSC22D3 can promote the resting state of HSCs by regulating the stability of p53. It remains elusive that how TSC22D3 plays a role in the regulation of the maintenance of HSCs in vitro, therefore, further investigations are required to depict its underlying mechanism. On this basis, We firstly plan to analyze the potential downstream targets of TSC22D3 in the maintenance of HSCs in vitro through RNA-seq based transcriptome comparison; then, we will verify the predicted targets of TSC22D3 through Co-IP, gene overexpression, gene knockdown, and signaling pathway activation/inhibition. Our project could contribute to an in-depth understanding of the quiescent maintenance mechanisms of HSPCs in vitro and provide ideas for the treatment of leukemia and other malignant hematological diseases.
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