Hypoxic Induction of the Regulator of G-Protein Signalling 4 Gene Is Mediated by the Hypoxia-Inducible Factor Pathway

Olechnowicz, Sam W. Z.; Fedele, Anthony O.; Peet, Daniel J.

doi:10.1371/journal.pone.0044564

Cited by 15 publications

(16 citation statements)

References 69 publications

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“…We have recently found, for example, that hyperthermia (heat shock) markedly alters the expression of several SZ, BD and ASD candidate genes, including ZNF804A , ARNT2 and SMARCA2 , in a model of the human fetal telencephalon derived from iPSCs [ 66 , 96 ]. In addition, in mouse models, gene x environment interactions involving the SZ, BD, and ASD candidate genes DISC1 , NRG1 , RGS4 , and AKT1 have been described [ 97 – 102 ].…”

Section: Discussionmentioning

confidence: 99%

ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin

et al. 2015

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ZNF804A (Zinc Finger Protein 804A) has been identified as a candidate gene for schizophrenia (SZ), autism spectrum disorders (ASD), and bipolar disorder (BD) in replicated genome wide association studies (GWAS) and by copy number variation (CNV) analysis. Although its function has not been well-characterized, ZNF804A contains a C2H2-type zinc-finger domain, suggesting that it has DNA binding properties, and consequently, a role in regulating gene expression. To further explore the role of ZNF804A on gene expression and its downstream targets, we used a gene knockdown (KD) approach to reduce its expression in neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs). KD was accomplished by RNA interference (RNAi) using lentiviral particles containing shRNAs that target ZNF804A mRNA. Stable transduced NPC lines were generated after puromycin selection. A control cell line expressing a random (scrambled) shRNA was also generated. Neuronal differentiation was induced, RNA was harvested after 14 days and transcriptome analysis was carried out using RNA-seq. 1815 genes were found to be differentially expressed at a nominally significant level (p<0.05); 809 decreased in expression in the KD samples, while 1106 increased. Of these, 370 achieved genome wide significance (FDR<0.05); 125 were lower in the KD samples, 245 were higher. Pathway analysis showed that genes involved in interferon-signaling were enriched among those that were down-regulated in the KD samples. Correspondingly, ZNF804A KD was found to affect interferon-alpha 2 (IFNA2)-mediated gene expression. The findings suggest that ZNF804A may affect a differentiating neuron’s response to inflammatory cytokines, which is consistent with models of SZ and ASD that support a role for infectious disease, and/or autoimmunity in a subgroup of patients.

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Section: Discussionmentioning

confidence: 99%

ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin

et al. 2015

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“…In this in vitro ischemia model, the growth medium of the cells was replaced with medium lacking glucose (HBSS Phenol red medium) and placed in a chamber that was rendered anaerobic by a sachet containing ascorbic acid (AnaeroGenTM, OXOID, Germany) [10]. Resazurin, an anaerobic indicator (OXOID, Germany) sensitive to changes in oxygen levels, was placed in the chamber and the lid of the chamber was tightly closed and placed in the incubator at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Cofilin Inhibition Restores Neuronal Cell Death in Oxygen–Glucose Deprivation Model of Ischemia

2014

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Ischemia is a condition associated with decreased blood supply to the brain, eventually leading to death of neurons. It is associated with a diverse cascade of responses involving both degenerative and regenerative mechanisms. At the cellular level, the changes are initiated prominently in the neuronal cytoskeleton. Cofilin, a cytoskeletal actin severing protein, is known to be involved in the early stages of apoptotic cell death. Evidence supports its intervention in the progression of disease states like Alzheimer's and ischemic kidney disease. In the present study, we have hypothesized the possible involvement of cofilin in ischemia. Using PC12 cells and mouse primary cultures of cortical neurons, we investigated the potential role of cofilin in ischemia in two different in vitro ischemic models: chemical induced oxidative stress and oxygen-glucose deprivation/reperfusion (OGD/R). The expression profile studies demonstrated a decrease in phosphocofilin levels in all models of ischemia, implying stress-induced cofilin activation. Furthermore, calcineurin and slingshot 1L (SSH) phosphatases were found to be the signaling mediators of the cofilin activation. In primary cultures of cortical neurons, cofilin was found to be significantly activated after 1 h of OGD. To delineate the role of activated cofilin in ischemia, we knocked down cofilin by siRNA technique and tested the impact of cofilin silencing on neuronal viability. Cofilin siRNA-treated neurons showed a significant reduction of cofilin levels in all treatment groups (control, OGD and OGD/R). Additionally, cofilin siRNA reduced cofilin mitochondrial translocation and caspase 3 cleavage, with a concomitant increase in neuronal viability. These results strongly support the active role of cofilin in ischemia-induced neuronal degeneration and apoptosis. We believe that targeting this protein mediator has a potential for therapeutic intervention in ischemic brain injury and stroke.

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“…The abundance of EPO mRNA was about 20-fold higher than in total kidneys of nontreated mice. In parallel, also the expression levels of other genes supposed to be triggered by HIF-2, such as adrenomedullin (ADM), cyclooxygenase-2 (COX-2), regulators of G-protein signaling (RGS) 2, 4, and 5, or PHD3, [32][33][34][35][36][37][38][39] were clearly increased. In glomeruli of mice Enzymes such as enolase 1 and lactate dehydrogenase 1 were also increased in Vhl-deficient glomeruli and remained elevated in glomeruli with an additional knockout of HIF-2α, suggesting that they were regulated by HIF-1.…”

Section: Inducible Deletion Of Vhl In Cx40-expressing Cellsmentioning

confidence: 99%

Inducible glomerular erythropoietin production in the adult kidney

Gerl

Miquerol

Todorov

et al. 2015

Kidney International

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Hypoxia-inducible factor (HIF)-2-triggered erythropoietin production in renal interstitial fibroblast-like cells is the physiologically relevant source of erythropoietin for regulating erythropoiesis. During renal fibrosis, these cells transform into myofibroblasts and lose their ability to produce sufficient erythropoietin leading to anemia. To find if other cells for erythropoietin production might exist in the kidney we tested for the capability of nonepithelial glomerular cells to elaborate erythropoietin. Therefore, HIF transcription factors were stabilized by cell-specific deletion of the von Hippel-Lindau (VHL) gene. Inducible deletion of VHL in glomerular connexin40-expressing cells (endothelial, renin-expressing, and mesangial cells) markedly increased glomerular erythropoietin mRNA expression levels, plasma erythropoietin concentrations, and hematocrit values. These changes were mimicked by inducible cell-specific VHL deletion in renin-expressing and in mesangial cells but not in endothelial cells. The increases of erythropoietin production were absent, when VHL was co-deleted with HIF-2. The induction of glomerular erythropoietin expression was associated with the downregulation of juxtaglomerular renin expression, again in a HIF-2-dependent manner. Thus, VHL deletion in renin-expressing and in mesangial cells induces the capability to produce relevant amounts of erythropoietin and to suppress renin expression in the adult kidney if HIF-2 is stabilized.

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Hypoxic Induction of the Regulator of G-Protein Signalling 4 Gene Is Mediated by the Hypoxia-Inducible Factor Pathway

Cited by 15 publications

References 69 publications

ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin

ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin

Cofilin Inhibition Restores Neuronal Cell Death in Oxygen–Glucose Deprivation Model of Ischemia

Inducible glomerular erythropoietin production in the adult kidney

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