ArticleClinical epigenetics2015
Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy.
Article in Clinical epigenetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
What it found
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Who cites it
61 citing papers in PubMed, 93 citations in OpenAlex.
- Identification of compounds that repress DUX4 expression in facioscapulohumeral muscular dystrophy.Scientific reports · 2026Article
- Proband Nanopore Long-Read Genome Sequencing Facilitates Preimplantation Genetic Testing for Facioscapulohumeral Muscular Dystrophy.Neurology. Genetics · 2026Article
- Transgenic mouse models for investigating human DUX4 expression during development and its roles in FSHD pathophysiology.Disease models & mechanisms · 2026Article
- Identification of compounds that repress DUX4 expression in facioscapulohumeral muscular dystrophy.bioRxiv : the preprint server for biology · 2026Article
- From Variant Interpretation to Biomarker Translation: Multi-omics Integration in Inherited Neuromuscular Diseases.Human mutation · 2026Review
- Review
- Diversity challenges and reconciles genetics in facioscapulohumeral muscular dystrophy.Journal of human genetics · 2025Review
- All-in-one vectors for epigenetic CRISPR inhibition ofMolecular therapy. Methods & clinical development · 2025Article
- DUX4 at 25: how it emerged from "junk DNA" to become the cause of facioscapulohumeral muscular dystrophy.Skeletal muscle · 2025Review
- Integrating D4Z4 methylation analysis into clinical practice: improvement of FSHD molecular diagnosis through distinct thresholds for 4qA/4qA and 4qA/4qB patients.Clinical epigenetics · 2024Article
- Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression.Human molecular genetics · 2024Article
- Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy.Brain : a journal of neurology · 2024Article
- Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy.Neurology · 2023Observational
- SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.Communications biology · 2023Article
- WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy.Nucleic acids research · 2023Article
- Facioscapulohumeral muscular dystrophy: the road to targeted therapies.Nature reviews. Neurology · 2023Review
- Article
- Update on the Molecular Aspects and Methods Underlying the Complex Architecture of FSHD.Cells · 2022Review
- FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?Journal of personalized medicine · 2022Review
- Spatio-temporal gait differences in facioscapulohumeral muscular dystrophy during single and dual task overground walking - A pilot study.Journal of clinical and translational research · 2022Article
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundBoth forms of facioscapulohumeral muscular dystrophy (FSHD) are associated with aberrant epigenetic regulation of the chromosome 4q35 D4Z4 macrosatellite. Chromatin changes due to large deletions of heterochromatin (FSHD1) or mutations in chromatin regulatory proteins (FSHD2) lead to relaxation of epigenetic repression and increased expression of the deleterious double homeobox 4 (DUX4) gene encoded within the distal D4Z4 repeat. However, many individuals with the genetic requirements for FSHD remain asymptomatic throughout their lives. Here we investigated family cohorts of FSHD1 individuals who were either affected (manifesting) or without any discernible weakness (nonmanifesting/asymptomatic) and their unaffected family members to determine if individual epigenetic status and stability of repression at the contracted 4q35 D4Z4 array in myocytes correlates with FSHD disease.
resultsFamily cohorts were analyzed for DNA methylation on the distal pathogenic 4q35 D4Z4 repeat on permissive A-type subtelomeres. We found DNA hypomethylation in FSHD1-affected subjects, hypermethylation in healthy controls, and distinctly intermediate levels of methylation in nonmanifesting subjects. We next tested if these differences in DNA methylation had functional relevance by assaying DUX4-fl expression and the stability of epigenetic repression of DUX4-fl in myogenic cells. Treatment with drugs that alter epigenetic status revealed that healthy cells were refractory to treatment, maintaining stable repression of DUX4, while FSHD1-affected cells were highly responsive to treatment and thus epigenetically poised to express DUX4. Myocytes from nonmanifesting subjects had significantly higher levels of DNA methylation and were more resistant to DUX4 activation in response to epigenetic drug treatment than cells from FSHD1-affected first-degree relatives containing the same contraction, indicating that the epigenetic status of the contracted D4Z4 array is reflective of disease.
conclusionsThe epigenetic status of the distal 4qA D4Z4 repeat correlates with FSHD disease; FSHD-affected subjects have hypomethylation, healthy unaffected subjects have hypermethylation, and nonmanifesting subjects have characteristically intermediate methylation. Thus, analysis of DNA methylation at the distal D4Z4 repeat could be used as a diagnostic indicator of developing clinical FSHD. In addition, the stability of epigenetic repression upstream of DUX4 expression is a key regulator of disease and a viable therapeutic target.
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