Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11731547_1.fastq.gz | Fastqsanger.gz | |||
| SRR11731547_2.fastq.gz | Fastqsanger.gz | |||
| SRR11731548_1.fastq.gz | Fastqsanger.gz | |||
| SRR11731548_2.fastq.gz | Fastqsanger.gz | |||
| SRR11731549_1.fastq.gz | Fastqsanger.gz |
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Project description:Hypoxia tolerance is mainly controlled by the hypoxia signaling pathway and HIF-1α/2α serve as master regulators in this pathway. Here we identify MYLIP, an E3 ubiquitin ligase thought to specifically target lipoprotein receptors, as a negative regulator of HIF-1α/2α. MYLIP interacts with HIF-1α/2α and catalyzes K27-linked polyubiquitination at lysine 118/442 (HIF-1α) or lysine 117 (HIF-2α). This modification induces proteasomal degradation of HIF-1α, resulting in inhibition of hypoxia signaling. Furthermore, Mylip-deficient bluntsnout bream, zebrafish and mice are more tolerant to hypoxia. These findings reveal a role for MYLIP in regulating hypoxia signaling and identify a target for developing fish strains with high hypoxia tolerance for the benefit of the
2024-12-04 | GSE283363 | GEO
Project description:Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin-remodeling, upon loss of the cardiolipin acyl transferase Tafazzin, mutes HIF-1a signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1a regulation but rather HIF-1a gene-expression, a dysfunction recapitulated in iPSCs-derived cardiomyocytes from Barth Syndrome patients with Tafazzin-deficiency. RNAseq analyses confirmed drastically altered signaling in Tafazzin mutant cells. In hypoxia, Tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-kB activation and concomitantly HIF-1a gene-expression. In agreement, Tafazzin-deficient mice hearts display reduced HIF-1a levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1a signaling through inactivation of a non-canonical signaling pathway: Lack of NF-kB activation through reduced mitochondrial ROS production diminishes HIF-1a transcription.
2018-09-12 | GSE119775 | GEO
Project description:Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis. HIF induces the expression of several hundred genes under hypoxic conditions. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered as a negative regulator of the hypoxia response pathway by formation of inactive dimers between the HIF-3α and HIF-1α or HIF-2α subunit. However, the human HIF3A mRNA is subject to complex alternative splicing, which leads to production of both long and short HIF-3α variants. It has been shown recently that the long HIF-3α variants can form αβ dimers that possess transcriptional activation capacity, while the short splice variant inhibits hypoxia-inducible gene expression. Chromatin immunoprecipitation analyses of HIF-3α2 overexpression in Hep3B cells show that HIF-3α2 binding associates with canonical hypoxia response elements (5'-RCGTG-3') in the promoter regions of the erythropoietin (EPO) gene among others. Luciferase reporter assays show that the identified HIF-3α2 chromatin-binding regions are sufficient to promote transcription by HIF-3α2 and HIF-1. Furthermore, HIF-3α2 overexpression and knock-down studies by siRNA targeting the HIF3A gene show that EPO mRNA and protein levels are upregulated and downregulated, respectively. Taken together, the results show that HIF-3α2 is a transcription activator that is directly involved in erythropoietin signaling.
2019-12-31 | GSE129491 | GEO
Project description:Cutaneous leishmaniasis (CL) is responsible for a significant burden of the global incidence of neglected tropical diseases, with 12 million people currently infected with Leishmania parasites. CL contains a spectrum of disease manifestations, ranging from self-healing skin lesions to permanent disfigurations. Currently there is no vaccine available, and many patients are refractory to treatment, emphasizing the need for new therapeutic targets. Previous work has demonstrated the necessity of macrophage HIF-alpha-mediated lymphangiogenesis to achieve efficient wound resolution during murine L. major infection. Here we investigate the role of macrophage HIF-alpha signaling separate from lymphangiogenesis, employing RNA-Seq transcriptome analysis on macrophages with intact or compromised HIF-alpha signaling, LysMCreARNTf/+ or LysMCreARNTf/f respectively, during L. major infection and under pro-inflammatory stimulus. We report that L. major infection alone is enough to induce HIF-alpha dependent transcriptomic changes while infection with L. major and pro-inflammatory stimuli administration instigates transcriptomic changes both dependent and independent of HIF-alpha signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found during L. major infection and in a pro-inflammatory environment, HIF-alpha suppresses pathways involved in protein translation such as the ribosome pathway and EIF2 signaling. Together this work supports infection with L. major induces a HIF-alpha transcriptomic program, but only in a pro-inflammatory environment does HIF-alpha suppress protein translation.
2024-11-01 | GSE273822 | GEO
Project description:Transcription mediated by hypoxia inducible factor (HIF-1) contributes to tumor angiogenesis and metastasis but is also involved in the activation of cell-death pathways and normal physiological processes. Given the complexity of HIF-1 signaling it could be advantageous to target a subset of HIF-1 effectors rather than the entire pathway. We compared the genome-wide effects of three molecules that each interfere with the HIF-1-DNA interaction: a polyamide targeted to the hypoxia response element (HRE), siRNA targeted to HIF-1α, and echinomycin, a DNA binding natural product with a similar but less specific sequence preference to the polyamide. The polyamide affects a subset of hypoxia-induced genes that are consistent with the binding site preferences of the polyamide. For comparison, siRNA targeted to HIF-1α and echinomycin each affect the expression of nearly every gene induced by hypoxia. Remarkably, the total number of genes affected by either polyamide or HIF-1α siRNA over a range of thresholds is comparable. The data shows how polyamides can be used to affect a subset of a pathway regulated by a transcription factor. In addition, this study offers a unique comparison of three complementary approaches towards exogenous control of endogenous gene expression. Experiment Overall Design: Hypoxia-mimetic DFO (deferoxamine)-stimulated U251 cells that were treated with polyamide 1, HIF-1α siRNA, and echinomycin were compared to control cells that were also DFO-stimulated. Cells not stimulated with DFO were also compared to the DFO-stimulated controls. Three biological replicates were included for each treatment/condition.
2008-06-15 | E-GEOD-7835 | biostudies-arrayexpress
Project description:Purpose: The goals of this study are to invsetigate the primary biological process and signalling pathway of HNRNPD. Results: Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis of the differential genes showed that the PI3K signaling pathway and HIF-1 signaling pathway were enriched after HNRNPD knockdown.
2024-07-06 | GSE271538 | GEO
Project description:The adaptive responses to oxygen depletion orchestrated by hypoxia-inducible factors (HIFs) produce profound effects on multiple pathways. A canonical metabolic response is enhanced fermentation, but this can generate an unfavorably acidic environment under poor capillary perfusion. It is unclear how cells balance the metabolic benefits of hypoxic responses against knock-on consequences on acid-base homeostasis. We studied the interplay between hypoxia and acidosis on HIF signaling in colorectal cancer cell lines that can survive acidic conditions. Hypoxia stabilized HIF-1α, but this effect was transient in combination with acidosis. By 48 h, HIF-1α induction decreased in proportion to acidification. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (CA9, PDK1), but these did not reflect a proteome-wide downregulation. Responses to acidosis and hypoxia were enriched in lysosomal proteins, but not proteasomal components, implicating the former degradation pathway in transient HIF-1α activation under acidosis. Moreover, HIF-1α decay was not due to decreased HIF1A transcription but was blocked by lysosomal inactivation (bafilomycin-A1). Acidotic hypoxia increased the abundance of lysosomes and activated autophagy by disabling the inhibitory influence of mammalian target of rapamycin complex 1, resulting in HIF-1α degradation. By blocking HIF-driven fermentative upregulation, this mechanism protects the cellular environment from deleterious acid-overloading, an outcome that outweighs the biosynthetic benefits of raised glycolytic flux under suppressed respiration. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling, but may not reflect tumor microenvironment chemistry. Consequently, acidic hypoxic tumor regions may not necessarily overlay with sites of HIF induction
2025-06-30 | PXD062474 | Pride
Project description:Natural control of HIV infection in Elite Controllers (EC) is a characteristic of <1% of HIV infected individuals. Extensive research has tried to elucidate the mechanism of control without any concrete results due to a large heterogeneity in the EC group, both between the sexes and how they obtain control. Therefore, we sought to identify signaling pathways associated with the EC phenotype by proteomics (all male) and transcriptomic (male and female) analysis. Further, we integrated the proteomics and transcriptomic analysis in the male cohort. We found that HIF signaling and downstream glycolysis are specific traits of the EC phenotype. Within this pathway ENO1 was upregulated in EC on a protein level irrespective of sex. We also performed targeted transcriptomic analysis where we identified HIF target genes as specifically de-regulation of in EC group. Namely, we observed an increase in the antiviral transcript GPS2, while CXCR4 and EIF5A were down regulated. Although we could not detect any difference in protein levels of HIF-1α in total PBMCs, we observed a higher portion of HIF-1α and HIF-1β in the nuclei of CD4+ and CD8+ T cells indicating an increased activation of HIF signaling in the male EC. Furthermore, the intracellular glucose levels were elevated in EC even as metabolite transporter expression of Glut1 and MCT-1 was decreased in lymphocytes showing that the EC have a unique metabolic uptake and secretion profile. Combined our data indicate the role HIF-1 signaling and glycolysis has in natural control of HIV infection.
2021-04-01 | PXD023990 | Pride
Project description:Fasting is a common dietary intervention known for its protective effects against metabolic and cardiovascular diseases. While its effects are mostly systemic, understanding tissue-specific changes in the heart is crucial for the identification of the mechanisms underlying fasting-induced cardioprotection. In this study, we performed a proteomic analysis to elucidate the proteome of the fasting heart. Our investigation identified a total of 4,652 proteins, with 127 exhibiting down-regulation and 118 showing up-regulation after fasting. Annotation analysis highlighted significant changes in processes such as lipid metabolism, the peroxisome pathway, and reactive oxygen species metabolism. Notably, the HIF-1 signaling pathway emerged as one of the focal points, with five affected proteins identified. Further experiments demonstrated down-regulation of HIF-1α at both transcript and protein levels. Intriguingly, while gene expression of Egln3 decreased, its protein product PHD3 remained unaffected by fasting. These findings underscore the regulation of the well-established cardioprotective HIF-1 signaling within the heart during 3-day fasting.
2024-10-08 | PXD050458 | Pride
Project description:Carbon-ion irradiation is an emerging therapeutic option for several tumor entities including lung cancer. Well oxygenated tumor areas compared to a hypoxic environment favor therapeutic photon irradiation efficiency of solid tumors due to increased amounts of DNA damage. The resistance of hypoxic tumor areas towards photon irradiation is enhanced through increased HIF-1 signaling. Here, we compared the effects of oxygen and HIF 1 after photon and carbon-ion irradiation with biological equivalent doses in a human non-small lung cancer model. In hypoxia compared to normoxia, A549 and H1299 cells displayed improved survival after photon irradiation. Knockdown of HIF-1M-NM-1 combined with photon irradiation synergistically delayed tumor growth in vivo. Photon irradiation induced HIF-1M-NM-1 and several of its target genes such as PDK1, GLUT-1, LDHA, and VEGF with subsequent enhanced tumor angiogenesis in vivo, a signaling cascade that was not targeted by carbon-ion irradiation. We present evidence that photons but not carbon-ions induce HIF-1M-NM-1 via mTOR pathway. Importantly, after carbon-ion irradiation in vivo, we observed substantial downregulation of HIF-1M-NM-1 and a drastically delayed tumor growth indicating a considerable higher relative biological effectiveness (RBE) than anticipated from the cell survival data. In sum, our results demonstrate that carbon-ions mediate an improved therapeutic response of tumor treatment compared to photon irradiation that is independent of cell oxygenation and HIF-1 signaling. 16 independent cell cultures were used. Each culture was split into an irradiated and a control plate, yieldin a total of 16 paired samples. Paired samples were analysed in 16 two-color hybridizations. Factors time (after irradiation) with levels 1h and 4h and factor radiation quality with levels C12 and X-rays were analyzed. Each of the 2x2 combinations was analyzed in 4 independent experiments.
2014-04-20 | E-GEOD-45403 | biostudies-arrayexpress