Expression of the transcription factor HIF-1α in NKp46+ innate lymphoid cells limits inflammation and fibrosis upon chronic colitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1061495 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27438015_1.fastq.gz | Fastqsanger.gz | |||
| SRR27438015_2.fastq.gz | Fastqsanger.gz | |||
| SRR27438016_1.fastq.gz | Fastqsanger.gz | |||
| SRR27438016_2.fastq.gz | Fastqsanger.gz |
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Project description:Innate lymphoid cells (ILCs) are critically involved in intestinal adaptation to microenvironmental challenges (Colonna, 2018; Guendel et al., 2020) and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by Hypoxia-inducible transcription factors (HIFs) the HIF-1α subunit shapes the ILC phenotype upon acute experimental colitis and contributes to intestinal damage. However, the impact of HIF signaling in NKp46+ ILC in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In a model of chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46+ ILC1s but a concomitant rise in neutrophils as well as Ly6C high macrophages. Single-nuclei RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes as well as intestinal stem cells. This was, furthermore, associated with increased BMP-integrin signaling, expansion of profibrotic fibroblasts subsets and intestinal fibrosis. In summary this suggests that HIF-1 α mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.
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Project description:The unbiased approach to determine transcriptional profiles of sorted NKp46+ cells from the small intestine of WT and HIF-1α KO mice.
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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-1α in colon, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-1α+/+, Hif-1αLSL/LSL mice. Background & Aims: The progression and growth of solid tumors leads to a state where tumors outgrow their capacity for efficient oxygenation and nutrient uptake and an increase in tumor hypoxia. Tumor hypoxic response is mediated by hypoxia-inducible factor (HIF)-1a and HIF-2a. These transcription factors regulate a battery of genes that are critical for tumor oxygenation, tumor metabolism, and cell proliferation and survival. Therefore, inhibitors of HIF have been sought for as anti-neoplastic agents in several different kinds of cancers. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1a is beneficial, and can reduce intestinal inflammation. The efficacy of pharmacological agents that chronically activate HIF-1a are decreased due to the tumorigenic potential of HIF. However, recent advance in understanding HIF signaling have identified mechanisms, which could allow for isoform specific activators. Activation of HIF-2a increases colon carcinogenesis and progression in mouse models. However, the role of chronic HIF-1a activation is unclear in the progression in colon cancer. The present data demonstrates that activation of HIF-1a in epithelial cells does not increase colon carcinogens or progression in two mouse models of colon cancer, and provides the proof of principle that HIF-1a activation maybe safe as therapies for inflammatory bowel disease. Global gene expression profiling in colon RNAs isolated from 6- to 8-week-old Hif-1α+/+ (n=5, Shah 019) and Hif-1αLSL/LSL (n=5, Shah 020).
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Project description:Analysis of Huh-7 hepatocarcinoma cell line depleted of NDRG3 or HIF-1α under hypoxic condition. HIF-1α and NDRG3 have distinct functions in hypoxia responses. Results provide insight into molecular basis of HIF-independent signaling in the development and progression of hypoxic tumors Gene expression profiles of Huh-7 cells stably expressing NDRG3-shRNA or HIF-1α-shRNA under normoxia were compared to gene expression profiles of Huh-7 stable cells under hypoxia for 6, 12 and 24 hours.
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Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of ccRCCs, leading to activation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCCs and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is necessary for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are necessary for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. Deficiency of HIF-2α increased CD8+ T cell infiltration and activation. These studies reveal different functions of HIF-1α and HIF-2α in ccRCC. SIGNIFICANCE The roles of HIF-1α and HIF-2α in ccRCC pathogenesis remain unclear. Using a mouse genetic approach we show that HIF-1α but not HIF-2α is important for tumour formation, contrary to predictions from studies of human ccRCC. We show that HIF-1α and HIF-2α transcriptionally regulate different aspects of metabolism and identify HIF-2α as a suppressor of immune cell infiltration and activation.
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Project description:Hypoxia-inducible factor-1 (HIF-1) is a master regulator of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits PHD3 to PKM2 to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with hnRNPF to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly rescues their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
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Project description:Hypoxia inducible factor-1α (HIF-1α) is a critical transcription factor for the hypoxic response, angiogenesis, normal hematopoietic stem cell regulation, and cancer development. Importantly, HIF-1α is also a key regulator for immune cell activation. In order to determine whether HIF-1α is sufficient for developing MDS phenotypes, we generated blood specific inducible HIF-1α transgenic mice. Using Vav1-Cre/Rosa26-loxP-Stop-loxP (LSL) rtTA driver, stable HIF-1α can be induced in a doxycycline administration dependent manner. After induction, HIF-1α-induced mice developed thrombocytopenia, leukocytopenia, macrocytic anemia, and multi-lineage dysplasia. We also found activation of both innate and adaptive immunity in HIF-1α- induced mice compared to those from control mice. Taken together, these data suggest that HIF-1α is sufficient to trigger a variety of key MDS features
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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.
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2022-02-26 | E-MTAB-11160 | biostudies-arrayexpress