Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4

Balog, Judit; Thijssen, Peter; Shadle, Sean C.; Straasheijm, Kirsten R.; Vliet, Patrick J. van der; Krom, Yvonne D.; Boogaard, Marlinde L. van den; Jong, Annika de; Lemmers, Richard J.L.F.; Tawil, Rabi; Tapscott, Stephen J.; Maarel, Silvère M. van der

doi:10.1080/15592294.2015.1113798

Cited by 53 publications

(78 citation statements)

References 41 publications

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“…Differences Between FSHD 1 and 2 FSHD1 and 2 have the same downstream disease mechanism, DUX4 derepression, yet there are some unique epigenetic responses with respect to the underlying genetic mechanism upstream. In FSHD2 but not in FSHD1, PRC2-mediated H3K27 trimethylation of D4Z4 seems to play a role in the disease [36]. This might have implications for drug development, depending on which target is chosen.…”

Section: The Role Of the Stage Of Cell Development And Dux4 Expressionmentioning

confidence: 99%

“…Furthermore, it has been shown that SMCHD1 protein levels decrease during muscle cell differentiation, correlating with DUX4 expression. Hence, differentiated muscle cells might be particularly prone to incomplete D4Z4 repression [36].…”

Section: The Role Of the Stage Of Cell Development And Dux4 Expressionmentioning

confidence: 99%

“…a) Modulating SMCHD1: In both types of FSHD myotube cultures, 2-to 3-fold overexpression of SMCHD1 resulted in a 70 to 90% reduction in DUX4 mRNA levels [36]. A 1.5-to 3-fold increase in SMCHD1 protein levels led to a significant decrease in DUX4 levels and that of its target genes.…”

Section: ) Enhance the Epigenetic Repression Of The D4z4mentioning

confidence: 99%

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Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.

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Section: The Role Of the Stage Of Cell Development And Dux4 Expressionmentioning

confidence: 99%

Section: The Role Of the Stage Of Cell Development And Dux4 Expressionmentioning

confidence: 99%

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Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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“…A muscle cell contribution to DUX4 in FSHD muscle biopsies is also likely, but via dynamic, stochastic DUX4 expression rather than the continuous expression seen in lymphocytes 32,40 . Time points for these transient bursts of DUX4 expression could include in satellite cells, when DUX4 expression may interfere with the normal function of the transcription factor PAX7 19,23,24 , and during myogenic differentiation, where DUX4 target gene expression may interfere with normal myogenesis 32,40,48 . Here we provide evidence for transient DUX4 expression at both these time points.…”

Section: Discussionmentioning

confidence: 99%

Lymphocytes contribute to DUX4 target genes in FSHD muscle biopsies

Banerji

Panamarova

Zammit

2019

Preprint

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dystrophy (FSHD) is an incurable myopathy linked to 22 overexpression of DUX4. However, DUX4 is difficult to detect in FSHD myoblasts and 23 target gene expression is not a consistent FSHD muscle biopsy biomarker, displaying 24 efficacy only on pathologically inflamed samples. Immune gene misregulation occurs in 25 FSHD muscle biopsies with DUX4 targets enriched for inflammatory processes. However, 26 assessment of the FSHD immune cell transcriptome, and the evaluation of DUX4 and target 27 gene expression has not yet been performed. We show that FSHD lymphoblastoid cell lines 28 (LCLs) display robust DUX4 expression, and express early and late DUX4 targets. 29 Moreover, genes elevated on FSHD LCLs are elevated in FSHD muscle biopsies, correlating 30 with DUX4 target activation and histological inflammation. These genes are importantly 31 unaltered in FSHD myoblasts/myotubes, implying a non-muscle source in biopsies. Our 32 results indicate an immune cell source of DUX4 and target gene expression in FSHD muscle 33 biopsies. 34 35 36Key Words: DUX4//FSHD/facioscapulohumeral muscular dystrophy/lymphocyte/skeletal 37 muscle 38 39 40Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent (12/100,000 1 ) inherited 41 skeletal myopathy. Clinically, FSHD manifests as a descending skeletal muscle atrophy, 42 commencing in the facial muscles before progressing to the shoulder girdle, associating with 43 scapular winging, and latterly the muscles of the lower limb, resulting in foot drop 2,3 . The 44 pattern of muscle involvement in FSHD is characteristically left/right asymmetric 4 . 45Heterogeneity in pathology progression among first degree relatives, including monozygotic 46 twins, is also well described [5][6][7] . Moreover, systemic disruption in FSHD pathology is 47 suggested by several extra-muscular features including retinal telangiectasia similar to Coat's 48 disease 8-10 and sensorineural hearing loss 11,12 . 49 50 FSHD shows an autosomal dominant pattern of inheritance linked to hypomethylation of the 51 D4Z4 macro-satellite at chromosome 4q35 2 . This epigenetic modification can be achieved in 52 two ways: ~95% of cases (FSHD1 -MIM 158900) have truncation of the D4Z4 region to 1-53 10 repeats 13 , while the remaining ~5% (FSHD2 -MIM 158901) carry mutations in chromatin 54 modifying genes such as SMCHD1 14 , or more rarely, DNMT3B 15 . In addition to D4Z4 55 hypomethylation, FSHD patients also carry a permissive 4qA haplotype, encoding a poly(A) 56 signal 13 . Each 3.3kb D4Z4 repeat unit encodes an open reading frame for the transcription 57 factor double homeobox 4 (DUX4). Epigenetic derepression of D4Z4 via hypomethylation 58 permits expression of DUX4 transcripts from the most distal repeat, which are then stabilised 59 by the poly(A) signal for translation. Mis-expression of DUX4 protein is thus proposed to 60 underlie FSHD pathology. 61 62 How DUX4 drives pathology in FSHD is poorly understood. DUX4 expression in myoblasts 63 has been shown to induce a set of genes which are pro-apoptotic 16-18 ...

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“…[120][121][122] FSHD1 is caused by a distinctive molecular mechanism affecting the subtelomeric region of chromosome 4q35 leading to DUX4 expression. 123,124 A large number of muscle MRI studies have been performed in patients with FSHD. [125][126][127][128][129][130][131] On MRI, the earliest and most affected muscles are the trapezius and serratus anterior followed by the latissimus dorsi and pectoralis major.…”

Section: Imaging and Pathological Correlationsmentioning

confidence: 99%

The Role of Muscle Imaging in the Diagnosis and Assessment of Children with Genetic Muscle Disease

Warman‐Chardon

Straub

2017

Neuropediatrics

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Muscle magnetic resonance imaging (MRI) and ultrasound (US) are emerging tools to assist in the diagnosis of children with genetic muscle disease. Increasing number of studies demonstrate that these imaging techniques can identify selective patterns of muscle atrophy, fatty degeneration, and muscle edema that help to distinguish between different early-onset genetic myopathies and muscular dystrophies. Recognizing patterns of pathology by muscle imaging can help to guide genetic testing and avoid the more invasive procedure of a muscle biopsy. Conversely, since massive parallel sequencing is now more commonly used as the initial step in diagnostic testing, imaging techniques can help to confirm or exclude if a variant of uncertain significance is indeed disease causing and compatible with a pattern of pathology as detected by muscle imaging. Whereas for diagnostic purposes and pattern recognition, muscle pathology does not need to be quantified, measuring disease progression is increasingly supported by quantitative muscle imaging, which is critical given the recent increment in rare disease therapeutic trials. Here, we discuss the value of muscle imaging techniques in pediatric muscle disease and summarize data identifying specific patterns of involvement in muscle MRI and US in some of the more common genetic myopathies and muscular dystrophies.

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Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4

Cited by 53 publications

References 41 publications

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Lymphocytes contribute to DUX4 target genes in FSHD muscle biopsies

The Role of Muscle Imaging in the Diagnosis and Assessment of Children with Genetic Muscle Disease

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