Deciphering transcription dysregulation in FSH muscular dystrophy

Ehrlich, Melanie; Lacey, Michelle

doi:10.1038/jhg.2012.74

Cited by 5 publications

(3 citation statements)

References 97 publications

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“…The initial DUX4 trigger in a single nucleus would thus be amplified through a transcriptional cascade that would extend to the whole myotube or myofiber and globally lead to muscle atrophy and inflammation, which are key features of FSHD. This concept is in agreement with a variant of the ‘majority rules’ model recently proposed by Ehrlich and Lacey which involved ‘oscillating non‐toxic generation of DUX4‐fl transcript throughout the FSHD myotube population’ .…”

Section: Discussionsupporting

confidence: 88%

DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?

Tassin

Laoudj-Chenivesse

Vanderplanck

et al. 2012

J Cellular Molecular Medi

124

125

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Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent hereditary muscle disorders. It is linked to contractions of the D4Z4 repeat array in 4q35. We have characterized the double homeobox 4 (DUX4) gene in D4Z4 and its mRNA transcribed from the distal D4Z4 unit to a polyadenylation signal in the flanking pLAM region. It encodes a transcription factor expressed in FSHD but not healthy muscle cells which initiates a gene deregulation cascade causing differentiation defects, muscle atrophy and oxidative stress. PITX1 was the first identified DUX4 target and encodes a transcription factor involved in muscle atrophy. DUX4 was found expressed in only 1/1000 FSHD myoblasts. We have now shown it was induced upon differentiation and detected in about 1/200 myotube nuclei. The DUX4 and PITX1 proteins presented staining gradients in consecutive myonuclei which suggested a diffusion as known for other muscle nuclear proteins. Both protein half-lifes were regulated by the ubiquitin-proteasome pathway. In addition, we could immunodetect the DUX4 protein in FSHD muscle extracts. As a model, we propose the DUX4 gene is stochastically activated in a small number of FSHD myonuclei. The resulting mRNAs are translated in the cytoplasm around an activated nucleus and the DUX4 proteins diffuse to adjacent nuclei where they activate target genes such as PITX1. The PITX1 protein can further diffuse to additional myonuclei and expand the transcriptional deregulation cascade initiated by DUX4. Together the diffusion and the deregulation cascade would explain how a rare protein could cause the muscle defects observed in FSHD.

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Section: Discussionsupporting

confidence: 88%

DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?

Tassin

Laoudj-Chenivesse

Vanderplanck

et al. 2012

J Cellular Molecular Medi

124

125

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“…Because FSHD Mb and Mt samples were shown to have highly significant dysregulation of expression of some of their genes relative to controls, 13 , 28 we compared their DNA methylation profiles (four FSHD to five normal controls and one disease-control; Fig. 1C and D).…”

Section: Resultsmentioning

confidence: 99%

Early de novo DNA methylation and prolonged demethylation in the muscle lineage

Tsumagari¹,

et al. 2013

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Myogenic cell cultures derived from muscle biopsies are excellent models for human cell differentiation. We report the first comprehensive analysis of myogenesis-specific DNA hyper- and hypo-methylation throughout the genome for human muscle progenitor cells (both myoblasts and myotubes) and skeletal muscle tissue vs. 30 non-muscle samples using reduced representation bisulfite sequencing. We also focused on four genes with extensive hyper- or hypo-methylation in the muscle lineage (PAX3, TBX1, MYH7B/MIR499 and OBSCN) to compare DNA methylation, DNaseI hypersensitivity, histone modification, and CTCF binding profiles. We found that myogenic hypermethylation was strongly associated with homeobox or T-box genes and muscle hypomethylation with contractile fiber genes. Nonetheless, there was no simple relationship between differential gene expression and myogenic differential methylation, rather only for subsets of these genes, such as contractile fiber genes. Skeletal muscle retained ~30% of the hypomethylated sites but only ~3% of hypermethylated sites seen in myogenic progenitor cells. By enzymatic assays, skeletal muscle was 2-fold enriched globally in genomic 5-hydroxymethylcytosine (5-hmC) vs. myoblasts or myotubes and was the only sample type enriched in 5-hmC at tested myogenic hypermethylated sites in PAX3/CCDC140 andTBX1. TET1 and TET2 RNAs, which are involved in generation of 5-hmC and DNA demethylation, were strongly upregulated in myoblasts and myotubes. Our findings implicate de novo methylation predominantly before the myoblast stage and demethylation before and after the myotube stage in control of transcription and co-transcriptional RNA processing. They also suggest that, in muscle, TET1 or TET2 are involved in active demethylation and in formation of stable 5-hmC residues.

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“…The molecular defect of type 1 FSHD (FSHD1) results from a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. D4Z4 contraction is considered pathogenic if it occurs on a specific chromosomal background, i.e., (i) the presence of a 4qA haplotype and (ii) a single nucleotide polymorphism that creates a polyadenylation site for the distal DUX4 transcript [8][9][10]. The pathological cut-off is conventionally determined at 10 RUs, and the majority of patients with FSHD1 carry 1-8 RUs on one allele [11].…”

Section: Introductionmentioning

confidence: 99%

Type 1 FSHD with 6–10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention

Salort‐Campana

Fatehi²,

Beloribi-Djefaflia³

et al. 2020

IJMS

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Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6–8 vs. 9–10 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6–8; Group 2, 9–10. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, p = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (>3.5) than those with low CSS (<1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.

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Deciphering transcription dysregulation in FSH muscular dystrophy

Cited by 5 publications

References 97 publications

DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?

DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?

Early de novo DNA methylation and prolonged demethylation in the muscle lineage

Type 1 FSHD with 6–10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention

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