A Novel HIF-2α/ARNT Signaling Pathway Protects Against Microvascular Dysfunction and heart failure After Myocardial Infarction
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ABSTRACT:
PROVIDER: PRJNA974849 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24681872_1.fastq.gz | Fastqsanger.gz | |||
| SRR24681872_2.fastq.gz | Fastqsanger.gz | |||
| SRR24681873_1.fastq.gz | Fastqsanger.gz | |||
| SRR24681873_2.fastq.gz | Fastqsanger.gz | |||
| SRR24681874_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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Project description:We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to investigate the influence of OEA on HIF-3A-ARNT.HDX-MS data indicated that OEA binding stabilized multiple residues within the Gβ and Fα regions of HIF-3A PAS-B domain.It is possible that the stabilized Gβ and Fα function as an “interlayer” to further contact with the AB-loop of ARNT.
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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).
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