ArticleHuman molecular genetics2016
The FMR1 promoter is selectively hydroxymethylated in primary neurons of fragile X syndrome patients.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 31 citations in OpenAlex.
- Mis-spliced FMR1 transcripts in human fragile X syndrome neural progenitors and neurons.Journal of neurodevelopmental disorders · 2026Article
- Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders.Science (New York, N.Y.) · 2025Article
- Transcriptomic profiling of unmethylated full mutation carriers implicates TET3 in FMR1 CGG repeat expansion methylation dynamics in fragile X syndrome.Journal of neurodevelopmental disorders · 2025Article
- Exploring the epigenetic landscape: The role of 5-hydroxymethylcytosine in neurodevelopmental disorders.Cambridge prisms. Precision medicine · 2024Review
- Antisense oligonucleotide rescue of CGG expansion-dependentProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Review
- Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases.Frontiers in aging neuroscience · 2022Review
- Implementation of fragile X syndrome carrier screening during prenatal diagnosis: A pilot study at a single center.Molecular genetics & genomic medicine · 2021Article
- DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome.International journal of molecular sciences · 2020Article
- Review
- The Contribution of Pluripotent Stem Cell (PSC)-Based Models to the Study of Fragile X Syndrome (FXS).Brain sciences · 2019Review
- 5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder.Human molecular genetics · 2018Article
- Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X.Scientific reports · 2018Article
- A Lexicon of DNA Modifications: Their Roles in Embryo Development and the Germline.Frontiers in cell and developmental biology · 2018Review
- Multifarious Functions of the Fragile X Mental Retardation Protein.Trends in genetics : TIG · 2017Review
- A C9ORF72 BAC mouse model recapitulates key epigenetic perturbations of ALS/FTD.Molecular neurodegeneration · 2017Article
- Fragile X-Associated Tremor/Ataxia Syndrome: From Molecular Pathogenesis to Development of Therapeutics.Frontiers in cellular neuroscience · 2017Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Fragile X syndrome (FXS) results from a repeat expansion mutation near the FMR1 gene promoter and is the most common form of heritable intellectual disability and autism. Full mutations larger than 200 CGG repeats trigger FMR1 heterochromatinization and loss of gene expression, which is primarily responsible for the pathological features of FXS . In contrast, smaller pre-mutations of 55–200 CGG are associated with FMR1 overexpression and Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative condition. While the role of 5-methylcytosine (5mC) in FMR1 gene silencing has been studied extensively, the role of 5-hydroxymethylation (5hmC), a newly discovered epigenetic mark produced through active DNA demethylation, has not been previously investigated in FXS neurons. Here, we used two complementary epigenetic assays, 5hmC sensitive restriction digest and ten-eleven translocation-assisted bisulfite pyrosequencing, to quantify FMR1 5mC and 5hmC levels. We observed increased levels of 5hmC at the FMR1 promoter in FXS patient brains with full-mutations relative to pre-mutation carriers and unaffected controls. In addition, we found that 5hmC enrichment at the FMR1 locus in FXS cells is specific to neurons by utilizing a nuclei sorting technique to separate neuronal and glial DNA fractions from post-mortem brain tissues. This FMR1 5hmC enrichment was not present in cellular models of FXS including fibroblasts, lymphocytes and reprogrammed neurons, indicating they do not fully recapitulate this epigenetic feature of disease. Future studies could investigate the potential to leverage this epigenetic pathway to restore FMR1 expression and discern whether levels of 5hmC correlate with phenotypic severity.
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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.