ArticlePloS one2015
FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 18 citations in OpenAlex.
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- Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease.NAR molecular medicine · 2024Article
- Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model.bioRxiv : the preprint server for biology · 2024Article
- Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort.Journal of neurology · 2024Article
- A new FRDA mouse model [Frontiers in neuroscience · 2023Article
- Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice.RNA biology · 2022Article
- Assessment of common housekeeping genes as reference for gene expression studies using RT-qPCR in mouse choroid plexus.Scientific reports · 2021Article
- Defining Transcription Regulatory Elements in the Human Frataxin Gene: Implications for Gene Therapy.Human gene therapy · 2020Article
- Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE-SunTag.Molecular therapy. Nucleic acids · 2018Article
- The role of oxidative stress in Friedreich's ataxia.FEBS letters · 2018Review
- Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia.Disease models & mechanisms · 2017Article
- Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich ataxia.Gene therapy · 2017Article
- Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor.Nucleic acids research · 2016Article
- Translating HDAC inhibitors in Friedreich's ataxia.Expert opinion on orphan drugs · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundFriedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues. METHODOLOGY / PRINCIPAL
findingsThe humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse. CONCLUSIONS / SIGNIFICANCE: Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.
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