Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA296908 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Injured peripheral neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such programs remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the pre-conditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knockout in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction reinnervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.
2016-01-21 | GSE73415 | GEO
Project description:<p>Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.</p><p><br></p><p>Linked study:</p><p><strong>UPLC-MS assay</strong> of mice kidney tissue sacrificed at<strong> day 10 </strong>after UIR is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3056' rel='noopener noreferrer' target='_blank'>MTBLS3056</a></p>
2021-07-22 | MTBLS3003 | MetaboLights
Project description:<p>Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.</p><p><br></p><p>Linked study:</p><p><strong>UPLC-MS assay</strong> of mice kidney tissues sacrificed at <strong>day 21 </strong>after UIR is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3003' rel='noopener noreferrer' target='_blank'>MTBLS3003</a></p>
2021-07-22 | MTBLS3056 | MetaboLights
Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas. Pre-treatment biopsies were collected from 16 human sarcoma. The gene expression analysis was performed using Illumina platform.
2011-08-29 | E-GEOD-31715 | biostudies-arrayexpress
Project description:Clioquinol (CQ) has been identified as a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1a specific asparaginyl hypoxylase (Factor inhibiting HIF-1, FIH-1). We previously showed that hypoxia coordinately regulate induction or repression of hypoxia-responsive genes by altering different types of methylations (H3K4me3, H3K9me3, and H3K27me3) at gene level. Here, we investigated CQ-mediated regulation of the expression of hypoxia-responsive genes and whether CQ had a similar effect on histone methylation and transcription of target genes under hypoxia.
2022-05-25 | GSE176557 | GEO
Project description:HIF-1α plays a crucial role in sustaining glioblastoma (GBM) cell growth and the maintenance of their undifferentiated phenotype. However, HIF-1α has been suggested to interplay with Wnt signaling components, thus activating a neuronal differentiation process in both GBM and normal brain. Here, we show that a β-catenin/TCF1/HIF-1α complex directly controls the transcription of neuronal differentiation genes in hypoxia. Conversely, at higher oxygen levels, the increased expression of TCF4 exerts a transcriptional inhibitory function on the same genomic regions, thus counteracting differentiation. Moreover, we demonstrate the existence of a positive correlation between HIF-1α, TCF1 and neuronal phenotype in GBM tumors, accompanied by the over-expression of several Wnt signaling components, finally impacting on patient prognosis. In conclusion, we unveil a mechanism by which TCF1 and HIF-1α induce a reminiscent neuronal differentiation of hypoxic GBM cells, which is hampered, in normoxia, by high levels of TCF4, thus de facto sustaining cell aggressiveness. In this study we unveil a tightly regulated mechanism by which HIF-1α controls the balance of Wnt signaling co-factors and how their molecular interplay regulates the peculiar transcriptional events responsible for the phenotypic shift of GBM stem cells toward a reminiscent neuronal differentiation, which might represent a future potential strategy to therapeutically weaken their aggressiveness.
2019-08-21 | GSE113512 | GEO
Project description:Chronic hypoxia induces pulmonary vascular remodeling and pulmonary hypertension (PH). While it is established that transcription factors, hypoxia-inducible factors (HIF-1α/HIF-2α) activate gene programs that drive hypoxia-induced PH, the mechanism of HIF-1/2 activation is less clear. Here, we report that carboxylterminus of Hsp70-interacting protein (CHIP or Stub1) modulates HIF-1α and HIF-2α transcription rather than reducing their stability. Knocking-down Stub1 reduced hypoxic activation of HIF-1α mRNA, protein, and activity while enhancing hypoxic induction of HIF-2α mRNA, protein, and target genes in pulmonary vascular cells. Mechanistically, CBP/p300-mediated acetylation of lysine (K287) inactivates the ubiquitin ligase activity of Stub1 and triggers its translocation from the cytoplasm into the nucleus. There, it recognizes the HIF promoter and hypoxia response elements (HREs) in target genes. Expression of Stub1-K287Q mutant (mimicking acetylation) enhanced hypoxia-induced HIF-1α expression, while acetyl-deficient Stub1-K287R mutant had the opposite effect on HIF-α but enhanced hypoxia-induced HIF-2α transcriptional activity. Endothelial-Stub1 transgenic mice tolerated chronic hypoxia better, had less pulmonary vascular remodeling, reduced pulmonary vascular resistance, and greater cardioprotection. Thus, Stub1 nuclear translocation enhances hypoxic induction of HIF-1α activity while suppressing deleterious effects of HIF-2α. These observations indicate that nuclear-Stub1 synergizes with HIF-1α to promote transcriptional responses and antagonizes HIF2α-driven PH in chronic hypoxia.
2023-04-01 | GSE221264 | GEO
Project description:Mesenchymal stromal cells (MSCs) are multipotent progenitors supporting bone marrow hematopoiesis. MSC have an efficient DNA damage response (DDR) and are consequently reatively radio-resistant cells. Therefore, MSCs are key to hematopoietic reconstitution following total body irradiation (TBI) and bone marrow transplantation (BMT). The bone marrow niche is hypoxic and via the heterodimeric transcription factor Hypoxia-inducible factor-1 (Hif-1), hypoxia enhances the DDR. Using gene knock-down, we have previously shown that the Hif-1α subunit of Hif is involved in MSC radio-resistance, however its exact mechanism of action remains unknown. In order to dissect the involvement of Hif-1α in the DDR, we have generated using CRISPR/Cas9 technology, a stable MS5 mouse MSC cell line lacking Hif-1 expression. Herein, we show that it is the whole Hif-1 transcription factor, and not only the Hif-1α subunit, that modulates the DDR of mouse MSCs, and that this effect is dependent upon the integrity of the DNA binding domain. We have also characterized the Hif-1α-dependent proteomic changes undergone by hypoxic MS5 cells. These findings have important implications for the modulation of MSC radio-resistance in the context of BMT and cancer.
2018-05-16 | PXD006701 | Pride
Project description:Clioquinol (CQ) has been identified as a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1a specific asparaginyl hypoxylase (Factor inhibiting HIF-1, FIH-1). We previously showed that hypoxia coordinately regulate induction or repression of hypoxia-responsive genes by altering different types of methylations (H3K4me3, H3K9me3, and H3K27me3) at gene level. Here, we investigated CQ-mediated regulation of the three histone methylations and whether CQ had a similar effect on histone methylation and transcription of target genes under hypoxia.
2022-05-25 | GSE176379 | GEO
Project description:Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1α-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Keywords: Hypoxia responsive, case control
2006-03-16 | GSE4086 | GEO