Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and the DUX4- and HA-binding protein C1QBP. These pathologies are prevented by 4-methylumbelliferone, an inhibitor of HA biosynthesis. Critically, 4-methylumbelliferone does not disrupt DUX4-C1QBP binding and has only a limited effect on DUX4 transcriptional activity, establishing that HA signaling has a central function in pathology and is a target for FSHD therapeutics.

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Identification of candidate miRNA biomarkers for facioscapulohumeral muscular dystrophy using DUX4-based mouse models

Disease Models & Mechanisms ◽

10.1242/dmm.049016 ◽

2021 ◽

Author(s):

Andreia M. Nunes ◽

Monique Ramirez ◽

Takako I. Jones ◽

Peter L. Jones

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Mouse Models ◽

Skeletal Muscles ◽

Facioscapulohumeral Muscular Dystrophy ◽

Muscle Pathology ◽

Aged Mouse ◽

Serum Samples ◽

Key Aspects ◽

Different Levels

Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of DUX4 in skeletal myocytes. As DUX4 is the key therapeutic target in FSHD, surrogate biomarkers of DUX4 expression in skeletal muscle are critically needed for clinical trials. While no natural animal models of FSHD exist, transgenic mice with inducible DUX4 expression in skeletal muscles rapidly develop myopathic phenotypes consistent with FSHD. Here, we establish a new, more accurate FSHD-like mouse model based on chronic DUX4 expression in a small fraction of skeletal myonuclei that develops pathology mimicking key aspects of FSHD across its lifespan. Utilizing this new aged mouse model and DUX4-inducible mouse models, we characterized the DUX4-related microRNA signatures in skeletal muscles, which represent potential biomarkers for FSHD. We found increased expression of miR-31-5p and miR-206 in muscles expressing different levels of DUX4 and displaying varying degrees of pathology. Importantly, miR-206 expression is significantly increased in serum samples from FSHD patients compared with healthy controls. Our data support miR-31-5p and miR-206 as new potential regulators of muscle pathology and miR-206 as a potential circulating biomarker for FSHD.

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The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-083118-014933 ◽

2019 ◽

Vol 20 (1) ◽

pp. 265-291 ◽

Cited By ~ 13

Author(s):

Charis L. Himeda ◽

Peter L. Jones

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Facioscapulohumeral Muscular Dystrophy ◽

Muscle Pathology ◽

Complex Interplay ◽

Aberrant Expression ◽

Early Human Development ◽

Pioneer Transcription Factor ◽

Chromatin Relaxation ◽

Early Human

Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, provides a powerful model of the complex interplay between genetic and epigenetic mechanisms of chromatin regulation. FSHD is caused by dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, aberrant expression of the DUX4 gene in skeletal muscle. DUX4 is a pioneer transcription factor that activates a program of gene expression during early human development, after which its expression is silenced in most somatic cells. When misexpressed in FSHD skeletal muscle, the DUX4 program leads to accumulated muscle pathology. Epigenetic regulators of the disease locus represent particularly attractive therapeutic targets for FSHD, as many are not global modifiers of the genome, and altering their expression or activity should allow correction of the underlying defect.

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