ArticleNucleic acids research2016
Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.Nature cell biology · 2026Article
- Simple sequence repeats and their expansions: role in plant development, environmental response and adaptation.The New phytologist · 2025Review
- Friedreich ataxia: clinical features and new developments.Neurodegenerative disease management · 2022Review
- 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
- Epigenetic Heterogeneity in Friedreich Ataxia Underlies VariableFrontiers in neuroscience · 2021Article
- Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells.The Journal of biological chemistry · 2020Article
- HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia.Frontiers in genetics · 2020Article
- Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models.Cell stress & chaperones · 2020Article
- Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups.Bioorganic & medicinal chemistry · 2017Article
- Friedreich Ataxia: current status and future prospects.Cerebellum & ataxias · 2017Review
- Translating HDAC inhibitors in Friedreich's ataxia.Expert opinion on orphan drugs · 2016Article
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
Friedreich ataxia, the most prevalent inherited ataxia, is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. Repressive chromatin spreads from the expanded GAA triplet-repeat sequence to cause epigenetic silencing of the FXN promoter via altered nucleosomal positioning and reduced chromatin accessibility. Indeed, deficient transcriptional initiation is the predominant cause of transcriptional deficiency in Friedreich ataxia. Treatment with 109, a class I histone deacetylase (HDAC) inhibitor, resulted in increased level of FXN transcript both upstream and downstream of the expanded GAA triplet-repeat sequence, without any change in transcript stability, suggesting that it acts via improvement of transcriptional initiation. Quantitative analysis of transcriptional initiation via metabolic labeling of nascent transcripts in patient-derived cells revealed a >3-fold increase (P < 0.05) in FXN promoter function. A concomitant 3-fold improvement (P < 0.001) in FXN promoter structure and chromatin accessibility was observed via Nucleosome Occupancy and Methylome Sequencing, a high-resolution in vivo footprint assay for detecting nucleosome occupancy in individual chromatin fibers. No such improvement in FXN promoter function or structure was observed upon treatment with a chemically-related inactive compound (966). Thus epigenetic promoter silencing in Friedreich ataxia is reversible, and the results implicate class I HDACs in repeat-mediated promoter silencing.
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