ArticleCell2023
Site-specific R-loops induce CGG repeat contraction and fragile X gene reactivation.
Article in Cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- The role of R-loops-mediated epigenetic regulation in genome stability maintenance and disease pathogenesis: a systematic review.Epigenetics · 2026Pooled it
- The novel role of GADD45A in the etiology of autism: modulating neuronal excitability via TET1/R-loop dependent regulation of KCNQ5.Molecular psychiatry · 2026Article
- Disruption of DNA Repair as an Emerging Epigenetic Mechanism Underlying Autism Spectrum Disorder.Current psychiatry reports · 2026Review
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- Integrative Analysis Reveals Conserved R-Loop Features in Mouse Embryonic Stem Cells.Epigenomes · 2026Article
- Repeat expansions inbioRxiv : the preprint server for biology · 2026Article
- Novel therapeutics in autism spectrum disorder.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Genetic and environmental influences in autism: guiding the future of tailored early detection and intervention.The Journal of clinical investigation · 2025Article
- Long-read sequencing reveals extensivebioRxiv : the preprint server for biology · 2025Article
- Article
- Therapeutic strategies for fragile X syndrome and implications for other gene-silencing disorders.Nature genetics · 2025Review
- Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells.Cell systems · 2025Article
- Review
- 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
- From Discovery to Innovative Translational Approaches in 80 Years of Fragile X Syndrome Research.Biomedicines · 2025Review
- Trinucleotide repeat expansion and RNA dysregulation in fragile X syndrome: emerging therapeutic approaches.RNA (New York, N.Y.) · 2025Review
- Review
- Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.PLoS genetics · 2025Article
- Prevalence of Fragile X syndrome in Georgian patients with autism spectrum disorder and/or intellectual disability: cross-sectional study and review of current approaches.Frontiers in pediatrics · 2025Article
- Looping forward: exploring R-loop processing and therapeutic potential.FEBS letters · 2025Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Here, we describe an approach to correct the genetic defect in fragile X syndrome (FXS) via recruitment of endogenous repair mechanisms. A leading cause of autism spectrum disorders, FXS results from epigenetic silencing of FMR1 due to a congenital trinucleotide (CGG) repeat expansion. By investigating conditions favorable to FMR1 reactivation, we find MEK and BRAF inhibitors that induce a strong repeat contraction and full FMR1 reactivation in cellular models. We trace the mechanism to DNA demethylation and site-specific R-loops, which are necessary and sufficient for repeat contraction. A positive feedback cycle comprising demethylation, de novo FMR1 transcription, and R-loop formation results in the recruitment of endogenous DNA repair mechanisms that then drive excision of the long CGG repeat. Repeat contraction is specific to FMR1 and restores the production of FMRP protein. Our study therefore identifies a potential method of treating FXS in the future.
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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.