ArticleHuman molecular genetics2013
A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Pharmacological treatments for Friedreich ataxia.The Cochrane database of systematic reviews · 2016Pooled it
- Review
- Selected Histone Deacetylase Inhibitors Reverse the Frataxin Transcriptional Defect in a Novel Friedreich's Ataxia Induced Pluripotent Stem Cell-Derived Neuronal Reporter System.Frontiers in neuroscience · 2022Article
- Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells.The Journal of biological chemistry · 2020Article
- Frataxin gene editing rescues Friedreich's ataxia pathology in dorsal root ganglia organoid-derived sensory neurons.Nature communications · 2020Article
- Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- The current state of biomarker research for Friedreich's ataxia: a report from the 2018 FARA biomarker meeting.Future science OA · 2019Review
- Synthetic transcription elongation factors license transcription across repressive chromatin.Science (New York, N.Y.) · 2017Article
- Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders.Molecular neurodegeneration · 2017Article
- Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming.Stem cells and development · 2016Article
- The infectious BAC genomic DNA expression library: a high capacity vector system for functional genomics.Scientific reports · 2016Article
- Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor.Nucleic acids research · 2016Article
- Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells.Human molecular genetics · 2015Article
- Neurodegenerative diseases in a dish: the promise of iPSC technology in disease modeling and therapeutic discovery.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2015Review
- Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists.Bioorganic & medicinal chemistry · 2015Article
- R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome.PLoS genetics · 2014Article
- Epigenetic-based therapies for Friedreich ataxia.Frontiers in genetics · 2014Review
- Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models.PloS one · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Friedreich's ataxia (FRDA) is caused by large GAA expansions in intron 1 of the frataxin gene (FXN), which lead to reduced FXN expression through a mechanism not fully understood. Understanding such mechanism is essential for the identification of novel therapies for FRDA and this can be accelerated by the development of cell models which recapitulate the genomic context of the FXN locus and allow direct comparison of normal and expanded FXN loci with rapid detection of frataxin levels. Here we describe the development of the first GAA-expanded FXN genomic DNA reporter model of FRDA. We modified BAC vectors carrying the whole FXN genomic DNA locus by inserting the luciferase gene in exon 5a of the FXN gene (pBAC-FXN-Luc) and replacing the six GAA repeats present in the vector with an ∼310 GAA repeat expansion (pBAC-FXN-GAA-Luc). We generated human clonal cell lines carrying the two vectors using site-specific integration to allow direct comparison of normal and expanded FXN loci. We demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. We applied the GAA-expanded reporter model to the screening of a library of novel small molecules and identified one molecule which up-regulates FXN expression in FRDA patient primary cells and restores normal histone acetylation around the GAA repeats. These results suggest the potential use of genomic reporter cell models for the study of FRDA and the identification of novel therapies, combining physiologically relevant expression with the advantages of quantitative reporter gene expression.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.