HTA2.0 (human transcriptome array) analysis of control iPSC-derived motor neurons (MN), FUS-H517D-hetero-iPSC-MN, and FUS-H517D-homo-iPSC-MNs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA485257 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To assess RNA regulation in the MN possessing mutated FUS-H517D gene. Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage stress and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular etiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, Bayesian gene regulatory networks (GRN) calculated by Super-Computer with transcriptome data sets of induced pluripotent stem cell (iPSC)-derived MNs possessing mutated FUSH517D (FUSH517D MNs) and FUSWT identified TIMELESS, PRKDC and miR-125b-5p as "hub genes" which influence fALS-FUS GRNs. miR-125b-5p expression up-regulated in FUSH517D MNs, showed opposite correlations against FUS and TIMELESS mRNA levels as well as reported targets of miR-125b-5p. In addition, ectopic introduction of miR-125b-5p could suppress mRNA expression levels of FUS and TIMELESS in the cells. Furthermore, we found TIMELESS and PRKDC among key players of DNA damage stress response (DDR) were down-regulated in FUSH517D MNs and cellular model analysis validated DDR under impaired DNA-PK activity promoted cytosolic FUS mis-localization to SGs. Our GRNs based on iPSC models would reflect fALS-FUS molecular etiology.
2021-04-19 | GSE118336 | GEO
Project description:Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular aetiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, both regular bioinformatics and Bayesian gene regulatory networks (GRN) analyses were applied to large-scale transcriptome datasets of induced pluripotent stem cell (iPSC)-derived MNs possessing wild-type form of FUS and mutated FUSH517D (FUSH517D MNs). From regular bioinformatics provided DNA damage response (DDR)-related genes were uniformly down-regulated in FUSH517D MNs. Bayesian GRN calculated by Super-Computer identified miR-125b-5p, TIMELESS and PRKDC as "hub genes/miRNA" which influence the GRNs. miR-125b-5p was up-regulated in FUSH517D MNs and negatively correlated with FUS, TIMELESS and miR-125b-5p target mRNAs. Introduction of miR-125b-5p suppressed Fus, Timeless and DDR-related genes in addition to miR-125b-5p targets in expression, and caused DNA damage. Furthermore, knocking-down Timeless expression caused DNA damage. PRKDC was down-regulated in FUSH517D MNs and the cellular model analyses validated DNA damage under impaired DNA-PK activity promoted FUS mis-localization to SGs. Collectively, our strategy with Bayesian GRNs based on the iPSC model would provide the first compelling evidence to elucidate fALS-FUSH517D molecular aetiology.
2021-04-19 | GSE125654 | GEO
Project description:Mutations in the RNA-binding protein FUS have been genetically linked to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease caused by the death of motoneurons (MNs). FUS is a ubiquitous protein and the mechanisms leading to selective MN loss downstream of FUS mutations are still largely unknown. We report the first transcriptome analysis of human purified MNs, obtained from isogenic induced Pluripotent Stem Cells (iPSCs) with a FUS wild-type or mutant genetic background. Gene ontology analysis of differentially expressed genes identified significant enrichment of pathways previously associated to other neurological diseases and non-FUS ALS, suggesting a common pathological mechanism. We also found several microRNAs deregulated in FUS mutant MNs and focused on miR-375 and miR-125b. Notably, miR-125b is a neural-enriched microRNA with multiple functions in the nervous system and miR-375 had been previously associated to MN survival. We report that relevant targets of both microRNAs, including the neural RNA-binding protein ELAVL4 and apoptosis factors such as p53, are aberrantly increased in FUS mutant MNs. Characterization of FUS RNA targets in the cell type primarily affected by the disease contributes to the definition of the pathogenic mechanisms of FUS-linked ALS.
2017-10-31 | GSE94888 | GEO
Project description:Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular aetiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, both regular bioinformatics and Bayesian gene regulatory networks (GRN) analyses were applied to large-scale transcriptome datasets of induced pluripotent stem cell (iPSC)-derived MNs possessing wild-type form of FUS and mutated FUSH517D (FUSH517D MNs). From regular bioinformatics provided DNA damage response (DDR)-related genes were uniformly down-regulated in FUSH517D MNs. Bayesian GRN calculated by Super-Computer identified miR-125b-5p, TIMELESS and PRKDC as "hub genes/miRNA" which influence the GRNs. miR-125b-5p was up-regulated in FUSH517D MNs and negatively correlated with FUS, TIMELESS and miR-125b-5p target mRNAs. Introduction of miR-125b-5p suppressed Fus, Timeless and DDR-related genes in addition to miR-125b-5p targets in expression, and caused DNA damage. Furthermore, knocking-down Timeless expression caused DNA damage. PRKDC was down-regulated in FUSH517D MNs and the cellular model analyses validated DNA damage under impaired DNA-PK activity promoted FUS mis-localization to SGs. Collectively, our strategy with Bayesian GRNs based on the iPSC model would provide the first compelling evidence to elucidate fALS-FUSH517D molecular aetiology.
2021-04-19 | GSE125653 | GEO
Project description:Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular aetiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, both regular bioinformatics and Bayesian gene regulatory networks (GRN) analyses were applied to large-scale transcriptome datasets of induced pluripotent stem cell (iPSC)-derived MNs possessing wild-type form of FUS and mutated FUSH517D (FUSH517D MNs). From regular bioinformatics provided DNA damage response (DDR)-related genes were uniformly down-regulated in FUSH517D MNs. Bayesian GRN calculated by Super-Computer identified miR-125b-5p, TIMELESS and PRKDC as "hub genes/miRNA" which influence the GRNs. miR-125b-5p was up-regulated in FUSH517D MNs and negatively correlated with FUS, TIMELESS and miR-125b-5p target mRNAs. Introduction of miR-125b-5p suppressed Fus, Timeless and DDR-related genes in addition to miR-125b-5p targets in expression, and caused DNA damage. Furthermore, knocking-down Timeless expression caused DNA damage. PRKDC was down-regulated in FUSH517D MNs and the cellular model analyses validated DNA damage under impaired DNA-PK activity promoted FUS mis-localization to SGs. Collectively, our strategy with Bayesian GRNs based on the iPSC model would provide the first compelling evidence to elucidate fALS-FUSH517D molecular aetiology.
2021-04-19 | GSE125652 | GEO
Project description:Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in ALS6 MNs. Furthermore, ALS6 MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of ALS6 MNs exposed to oxidative stress and partially restores the translation rates in ALS6 MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.
2024-01-26 | PXD038042 | Pride
Project description:FUS H517Q and healthy iPSC-derived motor neurons
| PRJNA838945 | ENA
Project description:The goal of this study is to find skate pectoral fin motor neuron markers. Total RNA was extracted from manually sorted pectoral fin MNs, which were retrogradely labeled and tail spinal cord cells. By comparing RNA expression profiles of pectoral fin MNs and tail spinal cord neurons, we could identity general MN, MN columnar, and subset MN pool markers for fin MNs.
2018-02-08 | GSE105156 | GEO
Project description:Spinal muscular atrophy (SMA) is characterized by low levels of survival motor neuron (SMN) protein and loss of motor neurons (MN); however, the underlying mechanism that links SMN deficiency to selective motor neuronal dysfunction is still largely unknown. We present here, for the first time, a comprehensive quantitative mass spectrometry study that covers the development of iPSC-derived MNs from both healthy individuals and SMA patients. We show an altered proteomic signature in SMA already at early stages during MN differentiation, associated with ER to Golgi transport, mRNA splicing and protein ubiquitination, in line with known SMA phenotypes. These alterations in the SMA proteome increase further towards later stages of MN differentiation. In addition, we find differences in altered protein expression between SMA patients, which however, have similar biological functions. Finally, we highlight several known SMN-binding partners as well as proteins associated with ubiquitin-mediated proteolysis and evaluate their expression changes during MN differentiation. Altogether, our work provides a rich resource of molecular events during early stages of MN differentiation, containing potentially therapeutically interesting protein expression profiles for SMA.
2022-02-15 | PXD015115 | Pride
Project description:In the central nervous system, motor neurons (MNs) are responsible for controlling essential body functions. Long noncoding RNAs have emerged overwhelmingly as gene expression regulators crucial at any step of MN differentiation and function. To uncover the function of the neuronal lncRNA nHOTAIRM1, abundantly expressed in spinal MNs, we generated, analysed and compared RNA-Seq data from wild type (WT) and nHOTAIRM1 knock-out (KO) MNs derived from iPSCs through a differentiaton protocol of 12 days
2023-11-22 | GSE228681 | GEO