ArticleHuman molecular genetics2015
Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 70 citations in OpenAlex.
- FXN protomutations are the source of pathogenic expanded GAA alleles in Friedreich ataxia and explain its unequal population distribution.Human molecular genetics · 2026Article
- Are neurodegenerative diseases late-onset neurodevelopmental disorders? Tracing the developmental origins of neuronal vulnerability.Frontiers in neuroscience · 2026Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Anti-gene oligonucleotides targeting Friedreich's ataxia expanded GAA⋅TTC repeats increase Frataxin expression.Molecular therapy. Nucleic acids · 2025Article
- MSH2 is not required for either maintenance of DNA methylation or repeat contraction at the FMR1 locus in fragile X syndrome or the FXN locus in Friedreich's ataxia.Epigenetics & chromatin · 2025Article
- Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.Brain : a journal of neurology · 2025Article
- Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.Current neurology and neuroscience reports · 2025Review
- Assessment of the Clinical Interactions of GAA Repeat Expansions inNeurology. Genetics · 2024Article
- A "Goldilocks Zone" for Recruiting BET Proteins with Bromodomain-1-Selective Ligands.ACS chemical biology · 2024Article
- Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease.NAR molecular medicine · 2024Article
- The Regulation of the Disease-Causing GeneCells · 2024Review
- Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers.Nucleic acids research · 2023Article
- Review
- A new FRDA mouse model [Frontiers in neuroscience · 2023Article
- Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich's ataxia.Human molecular genetics · 2022Article
- Review
- Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia.Journal of lipid research · 2022Article
- DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.Scientific reports · 2022Article
- NDF is a transcription factor that stimulates elongation by RNA polymerase II.Genes & development · 2022Article
- Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Friedreich's ataxia (FRDA) is a severe neurodegenerative disease caused by homozygous expansion of the guanine-adenine-adenine (GAA) repeats in intron 1 of the FXN gene leading to transcriptional repression of frataxin expression. Post-translational histone modifications that typify heterochromatin are enriched in the vicinity of the repeats, whereas active chromatin marks in this region are underrepresented in FRDA samples. Yet, the immediate effect of the expanded repeats on transcription progression through FXN and their long-range effect on the surrounding genomic context are two critical questions that remain unanswered in the molecular pathogenesis of FRDA. To address these questions, we conducted next-generation RNA sequencing of a large cohort of FRDA and control primary fibroblasts. This comprehensive analysis revealed that the GAA-induced silencing effect does not influence expression of neighboring genes upstream or downstream of FXN. Furthermore, no long-range silencing effects were detected across a large portion of chromosome 9. Additionally, results of chromatin immunoprecipitation studies confirmed that histone modifications associated with repressed transcription are confined to the FXN locus. Finally, deep sequencing of FXN pre-mRNA molecules revealed a pronounced defect in the transcription elongation rate in FRDA cells when compared with controls. These results indicate that approaches aimed to reactivate frataxin expression should simultaneously address deficits in transcription initiation and elongation at the FXN locus.
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Registered trials
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.