P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy
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ABSTRACT:
PROVIDER: PRJNA641972 | ENA |
REPOSITORIES: ENA
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Project description:Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.
2020-06-26 | GSE153301 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. Examine Dux4 full isoform binding sites in human fibroblast.
2012-01-03 | E-GEOD-33838 | biostudies-arrayexpress
Project description:DUX4 is generally agreed to underlie pathology in Facioscapulohumeral muscular dystrophy Microarrays were used to examine gene expression after primary murine satellite cell-derived myoblasts were retrovirally infected with constructs encoding DUX4, DUX4c, constitutively active, dominant negative and truncated DUX4 versions.
2017-01-31 | GSE77100 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. [Overexpression experiment] Quadruplicate total RNA samples were collected from control human primary myoblasts transduced with lentivirus carrying DUX4-fl, DUX4-s or GFP (MOI = 15) for 24 h and from untransduced myoblasts. [Defensin experiment] Quadruplicate samples were also collected from myoblasts and myotubes grown in media containing human beta-defensin 3 peptide or in control media.
2012-01-03 | E-GEOD-33799 | biostudies-arrayexpress
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an inherited progressive neuromuscular disorder that afflicts both children and adults regardless of gender. FSHD is caused by aberrant gain of expression of the transcription factor DUX4, which triggers a pro-apoptotic transcriptional program leading to muscle wasting. As today, no cure or therapeutic option is available to FSHD patients. Given its centrality in FSHD, blocking DUX4 expression with small molecule drugs is an attractive option. We previously showed that the long non-coding RNA DBE-T is required for aberrant DUX4 expression in FSHD. Using affinity purification followed by proteomics, we identified the chromatin remodeling protein WDR5 as a novel DBE-T interactor and a key player required for the biological activity of the lncRNA. We found that WDR5 is required for the expression of DUX4 and its targets in primary FSHD muscle cells. Moreover, targeting WDR5 rescues both cell viability and myogenic differentiation of FSHD patient cells. Notably, comparable results were obtained by pharmacological inhibition of WDR5. Importantly, WDR5 targeting was safe to healthy donor muscle cells. Our results support a pivotal role of WDR5 in the activation of DUX4 expression identifying a druggable target for an innovative therapeutic approach for FSHD.
2023-04-13 | GSE210610 | GEO
Project description:We investigated the effects of six weeks of voluntary wheel running in heterozygous B6(Cg)-Gt(ROSA)26Sortm1.1(DUX4*)Plj/J (FLExDUX4) mouse model of Facioscapulohumeral Muscular Dystrophy (FSHD) and their wild type (WT) littermates to characterize the structural/functional adaptations to voluntary wheel running and their molecular foundations using RNA sequencing
2023-12-01 | GSE233340 | GEO
Project description:The aim of this study is to define the molecular mechanisms underlying DUX4-associated toxicity in the context of facioscapulohumeral muscular dystrophy (FSHD). DUX4 is a transcription factor, which induces cell death by activating the transcription of its targets. No molecule able to directly control DUX4 activity is currently known. By using a tandem affinity purification protocol combined to mass spectrometry analysis, we identified Matrin 3 (MATR3), as the first cellular factor able to directly block DUX4 toxic activity. We found that MATR3 binds to the DNA binding domain of DUX4 blocking the activation of its genomic targets.
2023-08-21 | PXD011073 | Pride
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Experiment Overall Design: Comparison of the profiles of FSHD to 13 other conditions for disease-specific changes. The 13 conditions are NHM (Normal healthy muscle) n=15; JDM (Juvenile dermatomyositis) n=25; HSP (Human spastic paraplegia) n=4; FSHD (facioscapulohumeral dystrophy) unaffected n=5, affected n=9; FKRP (Fukutin related protein deficiency) n=7; ED-L (Emery-Dreifuss muscular dystrophy, lamin A/C deficiency) n=4; ED-E (Emery-Dreifuss muscular dystrophy, emerin deficiency) n=4; DYSF (dysferlinopathy) n=10; DMD (Duchenne Muscular Dystrophy) n=10; CALP (Calpain-3 deficiency) n=10; BMD (Becker Muscular Dystrophy) n=5; AQM (Acute quadriplegic myopathy) n=5; ALS (Amyotrophic lateral sclerosis) n=9.
2008-06-16 | E-GEOD-9397 | biostudies-arrayexpress
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is characterized by sporadic de-repression of the transcription factor DUX4 in skeletal muscle. We employed single-cell RNA-sequencing, combined with pseudotime trajectory modeling, to study FSHD disease etiology and cellular progression in human primary myocytes. We identified a small FSHD-specific cell population in all tested patient-derived cultures and detected new genes associated with DUX4 de-repression. We furthermore generated an FSHD cellular progression model, reflecting both the early burst-like DUX4 expression as well as the downstream activation of various FSHD-associated pathways, which allowed us to correlate DUX4 expression signature dynamics with that of regulatory complexes, thereby facilitating the prioritization of epigenetic targets for DUX4 silencing.
2018-12-03 | GSE122873 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.
2012-01-03 | GSE33838 | GEO