Loss of SMCHD1 in human muscle progenitor cells causes facioscapulohumeral muscular dystrophy disease phenotypes in the absence of DUX4 expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190830 | GEO | 2024/06/25
REPOSITORIES: GEO
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Project description:In human muscle, SMCHD1 mutations are associated with the onset of FSHD2, but the mechanism driving the disease onset remains unclear. A commonly accepted explanation is the loss of SMCHD1 binding to the D4Z4 locus activates the expression of DUX4 in FSHD2 muscle. In this study, we used human myoblasts having DUX4 non-permissive 4qB alleles as a model to study DUX4-independent functions of SMCHD1 on myoblast cell growth. Surprisingly, depletion of SMCHD1 in these cells resulted in a cell proliferation defect. Despite the absence of DUX4 target genes’ activation, these cells showed a repression of PAX7 target genes (a hallmark of FSHD) and similar changes in expression profile compared to FSHD myoblasts. Interestingly, downregulation of cell proliferation-related genes and dysregulation of fibroblasts-specific genes were observed in SMCHD1 knockdown myoblasts and FSHD2 myoblasts but not FSHD1 myoblasts. Additionally, we identified LAP2 as direct targets of SMCHD1. Depletion of LAP2 leads to cell proliferation defect similar to the effect after SMCHD1 knockdown. These data imply that DUX4 is not the only driver for the onset of FSHD, and SMCHD1 has DUX4-independent functions in muscle growth and development.
2024-06-25 | GSE190829 | GEO
Project description:In human muscle, SMCHD1 mutations are associated with the onset of FSHD2, but the mechanism driving the disease onset remains unclear. A commonly accepted explanation is the loss of SMCHD1 binding to the D4Z4 locus activates the expression of DUX4 in FSHD2 muscle. In this study, we used human myoblasts having DUX4 non-permissive 4qB alleles as a model to study DUX4-independent functions of SMCHD1 on myoblast cell growth. Surprisingly, depletion of SMCHD1 in these cells resulted in a cell proliferation defect. Despite the absence of DUX4 target genes’ activation, these cells showed a repression of PAX7 target genes (a hallmark of FSHD) and similar changes in expression profile compared to FSHD myoblasts. Interestingly, downregulation of cell proliferation-related genes and dysregulation of fibroblasts-specific genes were observed in SMCHD1 knockdown myoblasts and FSHD2 myoblasts but not FSHD1 myoblasts. Additionally, we identified LAP2 as direct targets of SMCHD1. Depletion of LAP2 leads to cell proliferation defect similar to the effect after SMCHD1 knockdown. These data imply that DUX4 is not the only driver for the onset of FSHD, and SMCHD1 has DUX4-independent functions in muscle growth and development.
2024-06-25 | GSE190828 | GEO
Project description:Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.
| S-EPMC3092836 | biostudies-literature
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with ?-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD.
| S-EPMC3606007 | biostudies-other
Project description:Purpose of reviewFacioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder, which is caused by incomplete repression of the transcription factor double homeobox 4 (DUX4) in skeletal muscle. To date, there is no DUX4-targeting treatment to prevent or delay disease progression. In the present review, we summarize developments in therapeutic strategies with the focus on inhibiting DUX4 and DUX4 target gene expression.Recent findingsDifferent studies show that DUX4 and its target genes can be repressed with genetic therapies using diverse strategies. Additionally, different small compounds can reduce DUX4 and its target genes in vitro and in vivo.SummaryMost studies that show DUX4 repression by genetic therapies have only been tested in vitro. More efforts should be made to test them in vivo for clinical translation. Several compounds have been shown to prevent DUX4 and target gene expression in vitro and in vivo. However, their efficiency and specificity has not yet been shown. With emerging clinical trials, the clinical benefit from DUX4 repression in FSHD will likely soon become apparent.
| S-EPMC7735392 | biostudies-literature
Project description:Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.
| S-EPMC3711615 | biostudies-literature
Project description:Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option.
| S-EPMC5023379 | biostudies-literature
Project description: Not available
| S-EPMC8631385 | biostudies-literature
Project description:FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD) characterized by the absence of a contraction in the D4Z4 macrosatellite repeat region on chromosome 4q35 that is the hallmark of FSHD1. However, hypomethylation of this region is common to both subtypes. Recently, mutations in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2. We identified a novel p.Lys275del SMCHD1 mutation in a family affected with FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a male who developed asymmetrical muscle weakness characteristic of FSHD at 13 years. Physical examination revealed marked bilateral atrophy at biceps brachii, bilateral scapular winging, some asymmetrical weakness at tibialis anterior and peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic changes. Endomysial and perivascular inflammation was found, which has been reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we conclude that the SMCHD1 mutation is the likely cause of the disease in this family.
| S-EPMC3851942 | biostudies-literature
Project description:Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.
| S-EPMC3671095 | biostudies-literature