Hypoxia Inducible Factor 1α-driven steroidogenesis impacts systemic hematopoiesis
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ABSTRACT:
PROVIDER: PRJNA1241793 | ENA |
REPOSITORIES: ENA
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Project description:Glucocorticoids regulate hematopoiesis, but how chronic elevation of endogenous glucocorticoid production affects hematopoietic stem cell (HSC) function and immune cell development remains incompletely understood. Using an adrenocortical cell-specific HIF1α (Hypoxia inducible Factor-1α)-deficient mouse model (P2H1Ad.Cortex) resulting in elevated glucocorticoid (GC) levels, we here demonstrate that sustained GC exposure promotes hematopoietic stem and progenitor cell (HSPC) expansion while shifting HSCs toward a more quiescent and metabolically restrained state. Functionally, these HSCs exhibited enhanced regenerative potential, as evidenced by superior donor chimerism in transplantation assays. In addition, we observed a striking increase in myeloid progenitors, as well as in their progeny (monocytes and granulocytes). Conversely, B-cell differentiation in the bone marrow was severely impaired, with a strong block at the pre-pro-B cell stage. To determine whether these phenotypes were driven by glucocorticoid receptor (GR) signaling, we performed transplantation experiments using GR-deficient or WT control bone marrow into P2H1Ad.Cortex or WT littermate recipients. This approach decisively demonstrated that both the increase in myeloid cells and the block in B-cell differentiation were GR-dependent, confirming that GC-GR signaling plays a pivotal role in shaping hematopoiesis. Taken together, our findings clearly suggest a direct role for chronic glucocorticoid exposure in regulating HSC function, lineage differentiation, and stress hematopoiesis. The mouse model of adrenocortical cell-specific HIF1α deficiency provides a valuable tool to study the long-term effects of elevated glucocorticoid levels on hematopoietic regulation and may provide further insight into hematologic disorders associated with chronic therapeutic glucocorticoid administration.
2025-09-03 | GSE292877 | GEO
Project description:The production of steroid hormones by the adrenal cortex is essential for maintaining homeostasis in response to stress. Disruptions to this process have been linked to various diseases, including congenital defects in steroid synthesis, Cushing syndrome, and adrenal tumors. Therefore, proper regulation of steroid hormone levels is essential for maintaining physiological balance and overall health. Hypoxia is a key regulator of adrenal steroidogenesis acting via the stabilization of HIF-1α transcription factors. We recently identified HIF-1α as a regulator of adrenal steroidogenesis through its control of specific microRNAs (miRNAs) that target key steroidogenic enzymes. However, the mechanisms by which HIF-1α influences miRNA expression remain unclear. To address this, we used the Cleavage Under Targets & Tagmentation (CUT&Tag) technique to map HIF-1α binding sites across the genome in a murine adrenocortical cell line. Our analysis of the HIF-1α binding profile revealed putative binding sites not only in classic steroidogenic gene loci, including Cyp11a1, but also in miRNA loci involved in steroid regulation. Crucially, HIF-1α-bound regions included genes involved in miRNA biogenesis and function, such as nuclear microprocessor and cytoplasmic RNA-induced silencing complex (RISC) components. Subsequent analysis of hypoxic transcriptomic profiles demonstrated widespread repression of these miRNA biogenesis and function genes by hypoxia, that could be modulated by HIF-1α. Based on our previous identification of HIF-1α as a regulator of adrenal steroidogenesis, our current findings further support its dual role in directly controlling steroidogenic gene expression via both transcriptional and posttranscriptional mechanisms. These results reinforce the HIF pathway as a master regulator of steroid hormone output under hypoxic conditions.
2025-11-30 | GSE311437 | GEO
Project description:HIF-1α CUT&Tag binding profile reveals a multifaceted regulation of steroidogenesis
| PRJNA1369459 | ENA
Project description:Ammonia is a toxic by-product of metabolism that causes cellular stress. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism that facilitate survival against toxicity have yet to be identified. We demonstrated that hypoxia-inducible factor-1α (HIF-1α) is stabilised and activated by ammonia stress. HIF-1α activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation and glutamine-dependent metabolism under ammonia stress in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1α counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1α in biphasic ammonia stress management in cancer stem-like cells. GS facilitates proliferation and HIF-1α contributes to metabolic remodelling in cellular energy usage resulting in attenuated proliferation but conversely promoting cell survival.
2017-11-22 | GSE107251 | GEO
Project description:Background: Intestine epithelial hypoxia-inducible factor-1α (HIF-1α) plays a critical role in maintaining gut barrier function. The aim of this study was to determine genetic activation of intestinal HIF-1α ameliorates western diet-induced metabolic dysfunction–associated steatotic liver disease (MASLD). Methods: Male and/or female intestinal epithelial-specific Hif1α overexpression mice (Hif1α LSL/LSL;VilERcre) and wild-type littermates (Hif1α LSL/LSL) were fed with regular chow diet, high fructose (HFr) or high-fat (60% Kcal) high-fructose diet (HFHFr) for 8 weeks. Metabolic phenotypes were profiled. Results: Male Hif1α LSL/LSL;VilERcre mice exhibited markedly improved glucose tolerance compared to Hif1α LSL/LSL mice in response to HFr diet. Eight weeks HFHFr feeding led to obesity in both Hif1α LSL/LSL;VilERcre and Hif1α LSL/LSL mice. However, male Hif1α LSL/LSL;VilERcre mice exhibited markedly attenuated hepatic steatosis along with reduced liver size and liver weight compared to male Hif1α LSL/LSL mice. Moreover, HFHFr-induced systemic inflammatory responses were mitigated in male Hif1α LSL/LSL;VilERcre mice compared to male Hif1α LSL/LSL mice and those responses were not evident in female mice. Ileum RNA-seq analysis revealed that glycolysis/gluconeogenesis was up in male Hif1α LSL/LSL;VilERcre mice accompanied by increased epithelial cell proliferation. Conclusion: Our data provide evidence that genetic activation of intestinal HIF-1α markedly ameliorates western diet-induced MASLD in a sex-dependent manner. The underlying mechanism is likely attributed to HIF-1α activation induced upregulation of glycolysis, which, in turn, leading to enhanced epithelial cell proliferation and augmented gut barrier function.
2024-10-26 | GSE280362 | GEO
Project description:Intestine epithelial specific hypoxia-inducible factor-1α overexpression on ileum transcriptome
| PRJNA1177978 | ENA
Project description:Hypoxia can result in tissue dysfunction, metabolic alterations, and structural damage within the pulmonary tissue, thereby impacting lung ventilation and air exchange. The identification of Hypoxia-inducible factor (Hif) 1α as a pivotal mediator in the inflammatory cascade subsequent to hypoxia induction has been established. However, the mechanism remains elusive. To delve deeper into this phenomenon, we have developed a murine model of sustained hypoxia and utilized nanocarriers for the delivery of lentivirus Hif-1α for knockdown purposes. Our findings suggest that under conditions of sustained hypoxia, knockdown of Hif-1α effectively ameliorated SpO2 levels and attenuated lung injury in our murine model. We observed that Hif-1α-mediated Histone Lactylation was evident in the lungs exposed to sustained hypoxia. Through RNA-seq and ChIP-seq profiling, we determined that upregulation of Hif-1α expression in sustained hypoxic lung tissue is essential for inducing lactylation enrichment of inflammatory response genes. Furthermore, knockdown of Hif-1α returned to normal inflammatory cytokines (e.g. TNF-α, IL-6 and IL-1β). Analysis of plasma metabolites from individuals experiencing restrictive/ obstructive lung disease revealed a significant enrichment of the Warburg effect within the sustained hypoxic group. Thus, our study provides compelling evidence supporting the notion that targeting Hif-1α-mediated histone lactylation may represent a promising therapeutic strategy for managing sustained hypoxia-induced lung injury.
2025-06-12 | GSE269142 | GEO
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
2018-12-25 | GSE83988 | GEO
Project description:Hypoxia can result in tissue dysfunction, metabolic alterations, and structural damage within the pulmonary tissue, thereby impacting lung ventilation and air exchange. The identification of Hypoxia-inducible factor (Hif) 1α as a pivotal mediator in the inflammatory cascade subsequent to hypoxia induction has been established. However, the mechanism remains elusive. To delve deeper into this phenomenon, we have developed a murine model of sustained hypoxia and utilized nanocarriers for the delivery of lentivirus Hif-1α for knockdown purposes. Our findings suggest that under conditions of sustained hypoxia, knockdown of Hif-1α effectively ameliorated SpO2 levels and attenuated lung injury in our murine model. We observed that Hif-1α-mediated Histone Lactylation was evident in the lungs exposed to sustained hypoxia. Through RNA-seq and ChIP-seq profiling, we determined that upregulation of Hif-1α expression in sustained hypoxic lung tissue is essential for inducing lactylation enrichment of inflammatory response genes. Furthermore, knockdown of Hif-1α returned to normal inflammatory cytokines (e.g. TNF-α, IL-6 and IL-1β). Analysis of plasma metabolites from individuals experiencing restrictive/ obstructive lung disease revealed a significant enrichment of the Warburg effect within the sustained hypoxic group. Thus, our study provides compelling evidence supporting the notion that targeting Hif-1α-mediated histone lactylation may represent a promising therapeutic strategy for managing sustained hypoxia-induced lung injury.
2025-06-12 | GSE269141 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE16432: MSI2 regulates hematopoiesis and accelerates leukemogenesis GSE22773: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible) GSE22774: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK) GSE22775: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines) Refer to individual Series
2010-07-21 | E-GEOD-22778 | biostudies-arrayexpress