Negative regulation of endothelial to haematopoietic transition by Nupr1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205595 | GEO | 2022/06/10
REPOSITORIES: GEO
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Project description:During early embryonic hematopoiesis, hematopoietic stem/progenitor cells (HSPCs) are considered to develop from hemogenic endothelial cells (HECs) though endothelial to hematopoietic transition (EHT). However, little is known about how EHT is regulated in human. Here, we report that GFI1 plays an essential role in ensuring EHT during hematopoietic differentiation of human embryonic stem cells (hESCs). GFI1 deletion in hESCs showed a complete EHT defect due to a closed chromatin state of hematopoietic genes in HECs. Further analysis revealed that GFI1 directly binds and maintains the open chromatin state of genes important for EHT, such as PI3K signaling. Together, our findings reveal an essential role of GFI1 mediated epigenetic mechanism underlying human EHT during hematopoiesis.
2021-12-01 | GSE189801 | GEO
Project description:During early embryonic hematopoiesis, hematopoietic stem/progenitor cells (HSPCs) are considered to develop from hemogenic endothelial cells (HECs) though endothelial to hematopoietic transition (EHT). However, little is known about how EHT is regulated in human. Here, we report that GFI1 plays an essential role in ensuring EHT during hematopoietic differentiation of human embryonic stem cells (hESCs). GFI1 deletion in hESCs showed a complete EHT defect due to a closed chromatin state of hematopoietic genes in HECs. Further analysis revealed that GFI1 directly binds and maintains the open chromatin state of genes important for EHT, such as PI3K signaling. Together, our findings reveal an essential role of GFI1 mediated epigenetic mechanism underlying human EHT during hematopoiesis.
2021-12-01 | GSE189800 | GEO
Project description:During early embryonic hematopoiesis, hematopoietic stem/progenitor cells (HSPCs) are considered to develop from hemogenic endothelial cells (HECs) though endothelial to hematopoietic transition (EHT). However, little is known about how EHT is regulated in human. Here, we report that GFI1 plays an essential role in ensuring EHT during hematopoietic differentiation of human embryonic stem cells (hESCs). GFI1 deletion in hESCs showed a complete EHT defect due to a closed chromatin state of hematopoietic genes in HECs. Further analysis revealed that GFI1 directly binds and maintains the open chromatin state of genes important for EHT, such as PI3K signaling. Together, our findings reveal an essential role of GFI1 mediated epigenetic mechanism underlying human EHT during hematopoiesis.
2021-12-01 | GSE189799 | GEO
Project description:Hematopoietic stem and progenitor cells (HSPCs) are required to establish and maintain the adult blood system in vertebrates. During development, HPSCs are generated from hemogenic endothelial cells that undergo an endothelial-to-hematopoietic transition (EHT). Growth factors and epigenetic changes can promote EHT, but these mechanisms do not explain its tight spatiotemporal regulation during development. Here, we show that microRNA (miR) miR-223-mediated regulation of N-glycan biosynthesis intrinsically restrains EHT, representing a new pathway that prevents excessive HSPC production. We find that miR-223 is uniquely expressed in hemogenic endothelial cells undergoing EHT and in nascent HSPCs. Loss of miR-223 promotes the expansion of these cells in the zebrafish and mouse aorta-gonad-mesonephros (AGM), where EHT occurs. miR-223 targets alg2 (alpha 1,3/ 1,6 mannosyltransferase) in the AGM endothelium to restrict hemogenic and HSPC specification. This enzyme is involved in the attachment of the N-glycans, a common co-translational modification9-12 that influences several pathophysiological processes, but has not yet been implicated in EHT. Using an N-glycosensor, we demonstrate that abundant protein N-glycan attachment occurs in vascular cells during EHT, and this process is required for HSPC production. High-throughput glycome analysis upon loss of miR-223 revealed that terminal alpha 1,3/6 mannose modifications are increased at the expense of alpha 2,3/6 sialic acid sugars. Importantly, pharmacological manipulation targeting these N-glycan types in wild-type embryos phenocopies the loss of miR-223 and enhances EHT as well as HSPC production. Thus, the N-glycome plays a previously unappreciated role as an intrinsic regulator of EHT, with specific mannose and sialic acid modifications serving as key endothelial determinants to restrict the hematopoietic fate.
2021-09-09 | GSE135246 | 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:In the advanced stages of cancer, autophagy is thought to promote tumor progression through its ability to mitigate various cellular stresses. However, the details of how autophagy is homeostatically regulated in such tumors are unknown. Here, we report that NUPR1 (nuclear protein 1, transcriptional regulator), a transcriptional coregulator, is aberrantly expressed in a subset of cancer cells and predicts low overall survival rates for lung cancer patients. NUPR1 regulates the late stages of autolysosome processing through the induction of the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE associated protein VAMP8. NUPR1 depletion deregulates autophagic flux and impairs autolysosomal clearance, inducing massive cytoplasmic vacuolization and premature senescence in vitro and tumor suppression in vivo. Collectively, our data show that NUPR1 is a potent regulator of autolysosomal dynamics and is required for the progression of some epithelial cancers.
2016-06-05 | GSE68873 | GEO
Project description:During embryonic development, blood cells emerge from a subset of specialized endothelial cells, named hemogenic endothelial cells (HECs), via a process known as endothelial-to-hematopoietic transition (EHT). A thorough characterization of HECs and their EHT is essential to guide the efforts to derive this population from human pluripotent stem cells (hPSCs), a critical step to generate therapeutic blood products in vitro. However, current known markers used to isolate HECs are insufficient as they also enrich for arterial endothelial cells that are associated with HECs. To identify specific human HEC markers, we performed transcriptomic analysis of 28-32-day human embryos, a developmental stage characterized by active EHT. We observed that the expression of FCGR2B, encoding for the Fc receptor CD32 previously associated with other specialized endothelia, is highly enriched in the ACE+CD34+ endothelial cell population that contains HECs. Functional ex vivo analyses confirmed that multilineage hematopoietic potential is highly enriched in CD32+ endothelial cells isolated from the aorta-gonad-mesonephros region and yolk sac of human embryos. In addition, CD32 emerged as selective marker for hPSC-derived HECs across different hematopoietic programs. Remarkably, our analyses showed that CD32 expression identifies HECs that are irreversibly bound to undergo EHT. As such, CD32 expression enriches for cells with hemogenic potential with a higher specificity for hPSC-derived HECs than other known HEC markers. These findings provide a simple method for isolating HECs from human embryos and hPSC cultures, allowing the efficient generation of hematopoietic cells in vitro.
2024-02-09 | GSE223222 | GEO
Project description:During embryonic development, blood cells emerge from a subset of specialized endothelial cells, named hemogenic endothelial cells (HECs), via a process known as endothelial-to-hematopoietic transition (EHT). A thorough characterization of HECs and their EHT is essential to guide the efforts to derive this population from human pluripotent stem cells (hPSCs), a critical step to generate therapeutic blood products in vitro. However, current known markers used to isolate HECs are insufficient as they also enrich for arterial endothelial cells that are associated with HECs. To identify specific human HEC markers, we performed transcriptomic analysis of 28-32-day human embryos, a developmental stage characterized by active EHT. We observed that the expression of FCGR2B, encoding for the Fc receptor CD32 previously associated with other specialized endothelia, is highly enriched in the ACE+CD34+ endothelial cell population that contains HECs. Functional ex vivo analyses confirmed that multilineage hematopoietic potential is highly enriched in CD32+ endothelial cells isolated from the aorta-gonad-mesonephros region and yolk sac of human embryos. In addition, CD32 emerged as selective marker for hPSC-derived HECs across different hematopoietic programs. Remarkably, our analyses showed that CD32 expression identifies HECs that are irreversibly bound to undergo EHT. As such, CD32 expression enriches for cells with hemogenic potential with a higher specificity for hPSC-derived HECs than other known HEC markers. These findings provide a simple method for isolating HECs from human embryos and hPSC cultures, allowing the efficient generation of hematopoietic cells in vitro.
2024-02-09 | GSE223221 | 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:Hematopoietic stem/progenitor cells (HSPCs) are generated from hemogenic endothelial cells (HECs) through endothelial-to-hematopoietic transition (EHT); however, the underlying mechanism remains poorly understood. Here, we report that HPC generation is significantly reduced in hPSC differentiatiation in a defined condition without vitamin C (Vc). Mechanistically, the endothelial cells generated in the absence of Vc fail to undergo EHT due to apparent failure in opening genomic loci essential for hematopoiesis. These loci exhibit abnormal accumulation of H3K27me3, a repressive histone modification due to lower activity of its demethylases. Consistently, deletion of H3K27me3 demethylases, JMJD3 and UTX, impaires HPC generation in the presence of Vc. Furthermore, Vc and jmjd3 are also important for HSC generation during zebrafish development. Together, we reveal an obligatory role of Vc underlying EHT process in hematopoisis and further support the important function of Vc during development.
2019-07-22 | GSE132969 | GEO