ArticleHuman molecular genetics2015
DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD.
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 35 papers.
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Who cites it
35 citing papers in PubMed, 48 citations in OpenAlex.
- Local Non-Coding Regulatory Elements in Muscular Dystrophies.International journal of molecular sciences · 2025Review
- A discrete region of the D4Z4 is sufficient to initiate epigenetic silencing.Human molecular genetics · 2025Article
- Deciphering Facioscapulohumeral Dystrophy in the clinical trials era: where are we now?Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2025Review
- Muscular Dystrophies.Advances in experimental medicine and biology · 2025Review
- Temporal variation in p38-mediated regulation of DUX4 in facioscapulohumeral muscular dystrophy.Scientific reports · 2024Article
- Natural antisense transcripts as versatile regulators of gene expression.Nature reviews. Genetics · 2024Review
- Oligonucleotide Therapies for Facioscapulohumeral Muscular Dystrophy: Current Preclinical Landscape.International journal of molecular sciences · 2024Review
- The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs.PLoS biology · 2023Article
- Facioscapulohumeral muscular dystrophy: the road to targeted therapies.Nature reviews. Neurology · 2023Review
- FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?Journal of personalized medicine · 2022Review
- Review
- DNA crosslinking and recombination-activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia.Cancer communications (London, England) · 2021Article
- Current Therapeutic Approaches in FSHD.Journal of neuromuscular diseases · 2021Review
- Promising Perspective to Facioscapulohumeral Muscular Dystrophy Treatment: Nutraceuticals and Phytochemicals.Current neuropharmacology · 2021Review
- Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy.Frontiers in pharmacology · 2021Review
- Cellular and animal models for facioscapulohumeral muscular dystrophy.Disease models & mechanisms · 2020Review
- Evaluation of blood gene expression levels in facioscapulohumeral muscular dystrophy patients.Scientific reports · 2020Article
- The prospects of targeting DUX4 in facioscapulohumeral muscular dystrophy.Current opinion in neurology · 2020Review
- Therapeutic Strategies Targeting DUX4 in FSHD.Journal of clinical medicine · 2020Review
- Tracking muscle wasting and disease activity in facioscapulohumeral muscular dystrophy by qualitative longitudinal imaging.Journal of cachexia, sarcopenia and muscle · 2019Article
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Authors and funding
9 authors at 6 institutions in 3 countries.
Funding
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the DUX4 transcription factor in skeletal muscle. The DUX4 retrogene is encoded in the D4Z4 macrosatellite repeat array, and smaller array size or a mutation in the SMCHD1 gene results in inefficient epigenetic repression of DUX4 in skeletal muscle, causing FSHD1 and FSHD2, respectively. Previously we showed that the entire D4Z4 repeat is bi-directionally transcribed with the generation of small si- or miRNA-like fragments and suggested that these might suppress DUX4 expression through the endogenous RNAi pathway. Here we show that exogenous siRNA targeting the region upstream of the DUX4 transcription start site suppressed DUX4 mRNA expression and increased both H3K9 methylation and AGO2 recruitment. In contrast, similarly targeted MOE-gapmer antisense oligonucleotides that degrade RNA but do not engage the RNAi pathway did not repress DUX4 expression. In addition, knockdown of DICER or AGO2 using either siRNA or MOE-gapmer chemistries resulted in the induction of DUX4 expression in control muscle cells that normally do not express DUX4, indicating that the endogenous RNAi pathway is necessary to maintain repression of DUX4 in control muscle cells. Together these data demonstrate a role of the endogenous RNAi pathway in repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat, and show that enhancing the activity of this pathway by supplying exogenous siRNA oligonucleotides represents a potential therapeutic approach to silencing DUX4 in FSHD.
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