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The Long-Form Hypoxia-Inducible Factor 3 Is a Transcription Activator that Regulates Erythropoietin Signaling

ABSTRACT: The Long-Form Hypoxia-Inducible Factor 3 Is a Transcription Activator that Regulates Erythropoietin Signaling

PROVIDER: PRJNA529069 | ENA |

REPOSITORIES: ENA

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Gamma aminobutyric acid increases erythropoietin overexpression of hypoxia inducible factors in rats

Project description:Gamma aminobutyric acid increases erythropoietin overexpression of hypoxia inducible factors in rats

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The Long-Form Hypoxia-Inducible Factor 3 Is a Transcription Activator that Regulates Erythropoietin Signaling

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-12-31 | GSE128847 | GEO

HIF-3α2 overexpression ChIP-seq in Hep3B cells and 1 % hypoxia

Project description:Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis. HIF induces the expression of several hundred genes under hypoxic conditions. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered as a negative regulator of the hypoxia response pathway by formation of inactive dimers between the HIF-3α and HIF-1α or HIF-2α subunit. However, the human HIF3A mRNA is subject to complex alternative splicing, which leads to production of both long and short HIF-3α variants. It has been shown recently that the long HIF-3α variants can form αβ dimers that possess transcriptional activation capacity, while the short splice variant inhibits hypoxia-inducible gene expression. Chromatin immunoprecipitation analyses of HIF-3α2 overexpression in Hep3B cells show that HIF-3α2 binding associates with canonical hypoxia response elements (5'-RCGTG-3') in the promoter regions of the erythropoietin (EPO) gene among others. Luciferase reporter assays show that the identified HIF-3α2 chromatin-binding regions are sufficient to promote transcription by HIF-3α2 and HIF-1. Furthermore, HIF-3α2 overexpression and knock-down studies by siRNA targeting the HIF3A gene show that EPO mRNA and protein levels are upregulated and downregulated, respectively. Taken together, the results show that HIF-3α2 is a transcription activator that is directly involved in erythropoietin signaling.

2019-12-31 | GSE129491 | GEO

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

Project description:Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

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Gamma aminobutyric acid increases erythropoietin overexpression of hypoxia inducible factors in rats

Project description:Erythropoietin (EPO) is the primary regulator of erythropoiesis in the mammalian fetus and the adult through interaction with erythropoietin receptor (EPOR). Deficiency of EPO induces anemia that is a major cause of death in patients with chronic kidney disease. Thus, development of safe treatment for anemia is an urgent issue. In this study, we investigated the effect of γ-aminobutyric acid (GABA) on serum EPO level and erythropoiesis, and its mechanism was elucidated in rat. GABA significantly (P < 0.05) increased EPO level in serum and expression levels of EPO and EPOR in a dose dependent manner. GABA increased the expression levels of HIF-1 and HIF-2 in a dose dependent manner compared with the negative control; while GABA did not affect the expression of prolyl-hydroxylase domain protein-2α (PHD-2α) gene, an oxygen sensor. GABA supplementation alters energy production pathway resulted in hypoxic condition, which increases EPO level in rat through overexpression of HIF-1 and HIF-2. This study shows a new physiological role of GABA in EPO production and thus GABA could contribute to the prevention of anemia by using alone or in combination with other anemia treating drugs.

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Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

Project description:Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in the mammalian brain. In clinical settings, recombinant EPO had revealed a remarkable improvement of cognitive functions, but the underlying mechanisms have remained obscure. Animal studies demonstrated, however, that neuronal EPO effects are independent of an elevated hematocrit. Here, we show with a novel line of reporter mice that cognitive challenge leads to local/endogenous hypoxia in hippocampal pyramidal neurons where it induces enhanced expression of both EPO and EPO receptor (EPOR). High-dose EPO administration, which amplifies auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO treatment is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. Taken together, this suggests a novel cellular model of neuroplasticity in which neuronal networks, challenged by cognitive tasks, drift into transient hypoxia which becomes a trigger of neuronal EPO/EPOR expression. This regulatory circle causes long-lasting neuroplastic adaptation, and as fundamental cellular mechanism, may be relevant for strategies aiming at cognitive improvement.

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2024-04-01 | GSE235438 | GEO