Total RNA sequencing of FXN knockdown or RNA editing gene knockdown in pulmonary artery endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171692 | GEO | 2021/04/09
REPOSITORIES: GEO
Similar Datasets
Project description:Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by mutations in the frataxin (FXN) gene. In this study, we immortalized mouse embryonic fibroblasts (MEFs) derived from G127V Fxn mutant mice and compared them to the wild-type (WT) MEFs. Mutant G127V MEFs demonstrated decreased cell proliferation and ATP production, as well as an increase in reactive oxygen species (ROS) production when compared to WT cells. These phenotypes are partially corrected by exogenous expression of frataxin. Surprisingly, extended passaging of immortalized G127V Fxn MEFs improves their proliferation, and alleviates ATP deficiency as well as decreases ROS levels despite persistent frataxin deficiency. We defined gene expression changes associated with phenotypic adaptation of G127V mutant MEFs by comparing transcriptional profiles of early and late passage G127V MEFs with WT cells.
2025-01-22 | GSE255810 | GEO
Project description:Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. Using chemical cross-linking (XL) accompanied with LC-MS/MS, we studied the the interaction between the core complexes Acp-ISD11-NFS1 (AIN) and AIN-ISCU (AINU) with FXN.
2018-07-11 | PXD006938 | Pride
Project description:Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. Using chemical cross-linking (XL) accompanied with LC-MS/MS, we studied the the interaction between the core complexes Acp-ISD11-NFS1 (AIN) and AIN-ISCU (AINU) with FXN.
2018-07-11 | PXD006928 | Pride
Project description:Total RNA sequencing of FXN knockdown or RNA editing gene knockdown in pulmonary artery endothelial cells
| PRJNA720606 | ENA
Project description:Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed genetic interaction mapping in control or FXN edited cells. This screen identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector.
2023-12-18 | GSE242192 | GEO
Project description:Friedreich's ataxia (FRDA), the most common inherited ataxia in humans, is caused by recessive mutations that lead to a substantial reduction in the levels of frataxin (FXN), a mitochondrial iron binding protein. FRDA is a multi-system disease, involving multiple neurological, cardiac, and metabolic manifestations whose study is hindered by a paucity of animal models that faithfully recapitulate human disease features. We developed an inducible (doxycycline) mouse model of Fxn deficiency (FRDAkd) that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. We performed microarray analysis of heart, cerebellum and dorsal root ganglia in FRDAkd mouse model of frataxin deficiency, and found several molecular pathway dysfunction via genome-wide transcriptome analyses. We also found that, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed. The rapidity of Fxn expression due to doxycycline removal and its robust correction of various parameters, even when restored after the onset of motor dysfunction, makes this FRDAkd mouse model an appealing potential preclinical tool for testing various therapeutics for FRDA.
2017-12-19 | GSE98790 | GEO
Project description:The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 owing to defective yolk sac and placental vascular development. Analysis of global gene expression revealed Frataxin (Fxn), the gene mutated in Friedreich’s ataxia (FRDA), as the most strongly downregulated gene in Ctcfdeficient placental endothelial cells. Moreover, in vitro reporter assays showed that Ctcf activates the Fxn promoter in endothelial cells. Reactive oxygen species (ROS) are known to accumulate in the endothelium of FRDA patients. Importantly, Ctcf deficiency induced ROS-mediated DNA damage in endothelial cells in vitro, and in placental endothelium in vivo. Taken together, our findings indicate that, Ctcf promotes vascular development, and limits oxidative stress in endothelial cells, perhaps through activation of Fxn transcription. These results reveal a function for a Ctcf–Fxn transcriptional pathway in vascular development, and also suggest a potential mechanism for endothelial dysfunction in FRDA.
2018-02-23 | GSE109510 | GEO
Project description:Friedreich's Ataxia (FRDA), a rare, inherited, progressive degenerative disease, is caused by a defective expression of mitochondrial protein frataxin (FXN), due to homozygous hyper-expansion of GAA triplets in the gene which severely reduce its transcription. FXN is crucial for cell survival and its deficiency in humans critically affects viability of neurons, cardiomyocytes and pancreatic beta cells. Around two thirds of individuals with FRDA show typical manifestation of hypertrophic cardiomyopathy, that can progress in heart failure and death. Except for FXN, very few genes have been correlated with ataxia and cardiac disease in FRDA. To identify other genes involved in pathogenesis of FRDA, a microarray analysis on FRDA patient's lymphoblastoid cells stably reconstituted with FXN was performed. HS-1 associated protein X-1 (HAX-1), a family of proteins playing important roles in the protection of cardiomyocytes from apoptosis, is the highest up-regulated transcript (FC=+2, p<0.0006). HAX-1 is highly expressed in heart and HAX-1 heterozygous-deficient hearts exhibit increases in infarct size. The microarray result was further assessed with qRT-PCR and western blot analysis performed on HEK293 stably transfected with empty vector or FXN-vector and lymphoblasts from FRDA patients compared to clinically unaffected heterozygous parents, confirming a strong co-expression of HAX-1 and FXN both at mRNA and protein level. Moreover, analysis of FXN and HAX-1 in peripheral blood mononuclear cells (PBMCs) of FRDA patients (n=13), heterozygous parents (n=6) and non-correlated healthy controls (n=13) revealed that their expressions are correlated. The positive correlation is more significant in FRDA patients showing a cardiac disease (10/13). The positive correlation between frataxin and HAX-1 expression level suggests a potential link of HAX-1 expression to pro-survival or protective cellular pathways related to frataxin. Thus, HAX-1 may be considered a specific biomarker of cardiomyopathy in FRDA and may represent a prognostic implement in these patients. Moreover, the discovery of novel genetic "risk" or "protective" factors in cardiomyopathy is crucial to improve risk stratification strategies and to identify new therapeutic targets.
2019-12-31 | GSE108200 | GEO
Project description:The inherited neurodegenerative disease Friedreichâ??s ataxia (FRDA) is caused by hyperexpansion of GAAâ?¢TTC trinucleotide repeats within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAAâ?¢TTC repeats causes heterochromatin-mediated silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts through retroviral transduction of transcription factors. FXN gene repression is maintained in the iPSCs, as are the mRNA and miRNA global expression signatures reflecting the human disease. GAAâ?¢TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme Msh2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in the iPSCs, occupies FXN intron 1, and shRNA silencing of Msh2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA. 65 samples from various number of tissue, primary cell lines undifferenatiated human embryonic stem cell lines, induces pluripotent stem cell lines have been run on Illumina HT12 v3 chips.
2010-07-30 | E-GEOD-22651 | biostudies-arrayexpress
Project description:Friedreich ataxia is a neuro and cardio degenerative disease, caused by progressive, decreased expression of the frataxin gene (FXN). Hyperthrophic cardiomyopathy is the major cause of early mortality. We used four different lines of human, Induced Pluripotent Stem Cells derived- cardiomyocytes which were transfected with an siRNA against frataxin post-differentiation. Trascriptome analysis of cells in which frataxin was knocked down vs cells transfected with a si control RNA allowed the identification of novel pathways that may contribute to the pathogenesis of the disease.
2022-11-02 | E-MTAB-11296 | biostudies-arrayexpress