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The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE235531 | GEO | 2023/11/08

REPOSITORIES: GEO

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The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions [EPAS1 scRNAseq]

Project description:To understand the role of the hypoxia-inducible transcription factor EPAS1 in regulating spermatogonial stem cell (SSC) function, a conditional knockout mouse was generated (EPAS1-cKO) where Epas1 was ablated only in the germ cells (Ddx4-Cre, Epasfl/-). For single cell RNA sequencing analysis, control and EPAS1-cKO males were pre-treated with the chemotherapeutic reagent busulfan to instigate regenerative conditions, and a germ cell-enriched cell population was collected 14 days later. Transcriptome profiling revealed that EPAS1 deficiency alters gene expression and key cellular processes in undifferentiated spermatogonia, including metabolism and proteostasis. Overall, these transcriptomic changes resulted in an impaired capacity for SSCs to restore spermatogenesis after busulfan treatment.

2023-11-08 | GSE235319 | GEO

The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions [Dstat bulkRNAseq]

Project description:In this study we explored the role of hypoxia and the hypoxia-inducible transcription factor EPAS1 in regulating spermatogonial stem cell (SSC) function in the mouse. We demonstrated that SSCs reside in hypoxic microenvironments in the testis through utilisation of the oxygen-sensing probe pimonidazole, and by confirming the stable presence of EPAS1, which is degraded at >5% O2. Here we stabilised EPAS1 expression in primary cultures of undifferentiated spermatogonia with the small drug molecule Daprodustat, providing a platform to identify genes whose expression is regulated by EPAS1 in SSCs.

2023-11-08 | GSE235453 | GEO

The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions [EPAS1 scRNAseq]

Project description:The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions [EPAS1 scRNAseq]

| PRJNA985690 | ENA

The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions

Project description:The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions

| PRJNA986326 | ENA

The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions [Dstat bulkRNAseq]

Project description:The hypoxia-inducible factor EPAS1 is required for normal spermatogonial stem cell function in regenerative conditions [Dstat bulkRNAseq]

| PRJNA986097 | ENA

Hypoxia and hypoxia inducible factor-1? are required for normal endometrial repair during menstruation.

Project description:Heavy menstrual bleeding (HMB) is common and debilitating, and often requires surgery due to hormonal side effects from medical therapies. Here we show that transient, physiological hypoxia occurs in the menstrual endometrium to stabilise hypoxia inducible factor 1 (HIF-1) and drive repair of the denuded surface. We report that women with HMB have decreased endometrial HIF-1? during menstruation and prolonged menstrual bleeding. In a mouse model of simulated menses, physiological endometrial hypoxia occurs during bleeding. Maintenance of mice under hyperoxia during menses decreases HIF-1? induction and delays endometrial repair. The same effects are observed upon genetic or pharmacological reduction of endometrial HIF-1?. Conversely, artificial induction of hypoxia by pharmacological stabilisation of HIF-1? rescues the delayed endometrial repair in hypoxia-deficient mice. These data reveal a role for HIF-1 in the endometrium and suggest its pharmacological stabilisation during menses offers an effective, non-hormonal treatment for women with HMB.

| S-EPMC5780386 | biostudies-literature

Convergent evolution on the hypoxia-inducible factor (HIF) pathway genes EGLN1 and EPAS1 in high-altitude ducks.

Project description:During periods of reduced O2 supply, the most profound changes in gene expression are mediated by hypoxia-inducible factor (HIF) transcription factors that play a key role in cellular responses to low-O2 tension. Using target-enrichment sequencing, we tested whether variation in 26 genes in the HIF signaling pathway was associated with high altitude and therefore corresponding O2 availability in three duck species that colonized the Andes from ancestral low-altitude habitats in South America. We found strong support for convergent evolution in the case of two of the three duck species with the same genes (EGLN1, EPAS1), and even the same exons (exon 12, EPAS1), exhibiting extreme outliers with a high probability of directional selection in the high-altitude populations. These results mirror patterns of adaptation seen in human populations, which showed mutations in EPAS1, and transcriptional regulation differences in EGLN1, causing changes in downstream target transactivation, associated with a blunted hypoxic response.

| S-EPMC6781116 | biostudies-literature

Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury.

Project description:Mild traumatic brain injury (TBI), also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO), the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1?), a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1? is regulated by NO via the mechanism of S-nitrosylation of HIF-1?. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO) and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1?. Exogenously administered GSNO was found not only to stabilize HIF-1? and to induce HIF-1?-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

| S-EPMC5461600 | biostudies-literature

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart.

Project description:Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1?. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1? into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1? or HIF-1?. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.

| S-EPMC3808664 | biostudies-literature

Endothelial Hypoxia-Inducible Factor-2α Is Required for the Maintenance of Airway Microvasculature.

Project description:BackgroundHypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents.MethodsThe tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1α or HIF-2α, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells.ResultsThe genetic deletion of Hif-2α but not Hif-1α caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2α promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2α deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2α or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2α in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation.ConclusionsOur findings reveal that the constitutive expression of endothelial HIF-2α is required for airway microvascular health.

| S-EPMC6340714 | biostudies-literature

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