A Liver Hepcidin-Intestinal HIF-2α Axis Regulates Iron Absorption During Systemic Iron Deficiency, Hypoxia and Hemochromatosis
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ABSTRACT:
PROVIDER: PRJEB29318 | ENA |
REPOSITORIES: ENA
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Project description:Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin (Hamp), a hepatic-derived hormone that controls iron mobilization through its molecular target, ferroportin (FPN), the only known mammalian iron exporter. Here, we took a transcriptomic approach to to compare the duodenal transcriptome during systemic iron demand to that of hepcidin-deficiency iron overload. Hampfl/fl (control) and AlbCreERT2;Hampfl/fl mice were placed on iron-replete and low-iron diets and were sacrificed two weeks following tamoxifen treatment. Duodenum RNA expression was compared across genotypes and across iron-replete and low iron diets.
2018-12-12 | E-MTAB-7329 | biostudies-arrayexpress
Project description:Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum.
2009-09-05 | GSE17969 | GEO
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.
2020-07-02 | PXD016630 | Pride
Project description:Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. We aimed to uncover the transcriptional program directing such tumor progression in chondrosarcomas. Here, we conducted weighted correlation network analysis (WGCNA) to extract a characteristic gene module underlying chondrosarcoma malignancy. We identified hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) as an upstream regulator that governs the malignancy gene module. HIF-2α was upregulated in high grade chondrosarcoma biopsies and HIF-2α gene amplification was associated with the poor prognosis of patients with chondrosarcoma. Using tumor xenograft mouse models, we demonstrated that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Pharmacological inhibition of HIF-2α in conjunction with the chemotherapy agents synergistically enhanced chondrosarcoma cell apoptosis and abolished malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of novel molecular-targeted therapeutics for chondrosarcoma.
2020-08-21 | GSE156565 | GEO
Project description:Bone is a highly dynamic tissue undergoing continuous formation and resorption. Here, we investigated differential but complementary roles of hypoxia-inducible factor (HIF)-1α and HIF-2α in regulating bone remodeling. Using RNA-seq analysis, we identified that specific genes involved in regulating osteoblast differentiation were similarly but slightly differently governed by HIF-1α and HIF-2α. We found that increased HIF-1α expression inhibited osteoblast differentiation via inhibiting RUNX2 function by upregulation of Twist2, confirmed using Hif1a conditional knockout (KO) mouse. Ectopic expression of HIF-1α via adenovirus transduction resulted in the increased expression and activity of RANKL, while knockdown of Hif1a expression via siRNA or osteoblast-specific depletion of Hif1a in conditional KO mice had no discernible effect on osteoblast-mediated osteoclast activation. The unexpected outcome was elucidated by the upregulation of HIF-2α upon Hif1a overexpression, providing evidence that Hif2a is a transcriptional target of HIF-1α in regulating RANKL expression, verified through an experiment of HIF-2α knockdown after HIF-1α overexpression. The above results were validated in an ovariectomized- and aging-induced osteoporosis model using Hif1a conditional KO mice. Our findings conclude that HIF-1α plays an important role in regulating bone homeostasis by controlling osteoblast differentiation, and in influencing osteoclast formation through the regulation of RANKL secretion via HIF-2α modulation.
2024-07-10 | GSE271730 | GEO
Project description:Radiotherapy continues to be a common treatment modality for cancer despite skeletal complications. Currently, there are no effective treatments for radiation-induced bone loss. Radiation induces substantial changes to the bone microenvironment; however, the effects of these changes on skeletal progenitors and their descendants remain elusive. Following radiation, LeprCre skeletal progenitors and their descendants, localize to hypoxic regions and exhibit HIF-2α stabilization, thus implicating a role for HIF-2α in radiation-induced bone loss. To test whether HIF-2α deficiency rescues radiation-induced bone loss, we conditionally ablated HIF-2α in LeprCre-expressing cells and their descendants. Compared to irradiated controls, irradiated LeprCre;Hif-2αfl/fl knock out mice demonstrate increased bone mass with values comparable to non-irradiated animals. Mechanistically, HIF-2α negatively regulates osteoblastogenesis, mineralization, and number of skeletal progenitors. To test whether HIF-2α can be targeted therapeutically, we administered PT2399, a potent and selective HIF-2α inhibitor whose structural analog belzutifan, has recently received FDA approval. Administration of PT2399 was sufficient to prevent radiation-induced bone loss in a single-limb irradiation model. As ~90% of patients on HIF-2α inhibitor treatment develop anemia, we constructed a PT2399-loaded bone-targeting nanocarrier (Aln-PT-NC) to increase on-target efficacy and reduce off-target kidney toxicity. Delivery of Aln-PT-NC completely prevented radiation-induced bone loss while reducing drug accumulation in the kidney. In this study, we identify HIF-2α as a negative regulator of bone formation in LeprCre skeletal progenitors and their descendants following radiotherapy and developed a bone-targeting HIF-2α therapeutic. Together, these studies highlight the clinical potential of Aln-PT-NC to be translated into a treatment regimen for bone radioprotection.
2023-06-24 | GSE235292 | GEO
Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).
2013-02-28 | E-GEOD-43416 | biostudies-arrayexpress
Project description:mRNA TE and steady-state levels were measured in hypoxic U87MG cells treated with non-silencing control or HIF-2α-specific or HIF-1α-specific siRNA pools followed by ribosome density fractionation.
2020-04-23 | GSE128555 | GEO
Project description:Growing number of cancer (stem) cells and stem cells were described to accommodate constituent active HIF-2α under normoxia. Previous study of hypoxia effect may have obscured some of normoxic HIF-2α functions as hypoxia inducible features. Our interest in study of protective potential of HIFs in lung cells led us to discover pseudohypoxia functions of HIF-2α under normoxia in human bronchial epithelial cells which exhibit pluripotency related markers and features. Our study provided perspective to pseudohypoxia functions of HIF-2α via enrichment of de novo motifs. In addition to the C-TAD, the N-TAD of HIF-2α was found to contribute to targeting on these non-canonical loci. Further elucidation of pseudohypoxia mechanism could resolve its implication of malignancy or pluripotency.
2016-07-06 | GSE81635 | GEO
Project description:10 days old tumor spheroids were processed for RNA isolation using the Quiagen RNeasy Micro Kit and cDNA synthesis was done using the Ambion WT Expression Kit. Wt, HIF-1α k/d and HIF-2α k/d samples were compared to each other.
2014-11-30 | GSE54360 | GEO