scholarly journals β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

2015 ◽  
Vol 12 (102) ◽  
pp. 20140797 ◽  
Author(s):  
Christopher R. S. Banerji ◽  
Paul Knopp ◽  
Louise A. Moyle ◽  
Simone Severini ◽  
Richard W. Orrell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Protein Interactions ◽  
Molecular Model ◽  
Meta Analysis ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Aberrant Expression ◽  
Incurable Disease ◽  
Therapeutic Development ◽  
Network Rewiring

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring ( InSpiRe ), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe , we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4 , gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.

scholarly journals Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (23) ◽  
pp. e2441-e2447 ◽  
Author(s):  
Kohei Hamanaka ◽  
Darina Šikrová ◽  
Satomi Mitsuhashi ◽  
Hiroki Masuda ◽  
Yukari Sekiguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Target Gene ◽  
Disease Gene ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Target Gene Expression ◽  
D4z4 Repeat ◽  
Biopsy Examination ◽  
Chromatin Relaxation

ObjectiveFacioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.MethodsClinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.ResultsA homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression.ConclusionLRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.

scholarly journals Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e82071 ◽  
Author(s):  
Félix F. González-Navarro ◽  
Lluís A. Belanche-Muñoz ◽  
Karen A. Silva-Colón
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Facioscapulohumeral Muscular Dystrophy

scholarly journals Mendelian randomization identifies folliculin expression as a mediator of diabetic retinopathy

2020 ◽  
Author(s):  
Andrew D. Skol ◽  
Segun C. Jung ◽  
Ana Marija Sokovic ◽  
Siquan Chen ◽  
Sarah Fazal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetic Retinopathy ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Susceptibility Gene ◽  
Glucose Response ◽  
Aberrant Expression ◽  
Genome Wide ◽  
A Genome

AbstractThe goal of the study was to identify genes whose aberrant expression can contribute to diabetic retinopathy. We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes (T1D) with and without retinopathy. Those genes exhibiting the largest difference in glucose response between individuals with diabetes with and without retinopathy were assessed for association to diabetic retinopathy utilizing genotype data from a genome-wide association study meta-analysis. All genetic variants associated with gene expression (expression Quantitative Trait Loci, eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. We show that expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy compared to individuals with diabetes without retinopathy. Three large, independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs to diabetic retinopathy. Mendelian randomization further confirmed a direct positive effect of increased FLCN expression on retinopathy in individuals with diabetes. Together, our studies integrating genetic association and gene expression implicate FLCN as a disease gene for diabetic retinopathy.

scholarly journals A Pediatric Review of Facioscapulohumeral Muscular Dystrophy

2017 ◽  
Vol 16 (04) ◽  
pp. 222-231 ◽  
Author(s):  
Yi-Wen Chen ◽  
Jean Mah
Keyword(s):  
Muscular Dystrophy ◽  
Severe Disease ◽  
Treatment Options ◽  
Standard Of Care ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Large Deletion ◽  
Current Standard ◽  
Aberrant Expression ◽  
Clinical Endpoints ◽  
Independent Ambulation

AbstractFacioscapulohumeral dystrophy is one of the most common forms of muscular dystrophies worldwide. It is a complex and heterogeneous disease secondary to insufficient epigenetic repression of D4Z4 repeats and aberrant expression of DUX4 in skeletal muscles. Type 1 facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of D4Z4 repeats on 4q35, whereas type 2 FSHD is associated with mutations of the SMCHD1 or DNMT3B gene in the presence of a disease-permissive 4qA haplotype. Classical FSHD is a slowly progressive disorder with gradual-onset of muscle atrophy and a descending pattern of muscle weakness. In contrast, early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement. However, the correlation between D4Z4 repeats and disease severity remains imprecise. The current standard of care guidelines offers comprehensive assessment and symptomatic management of secondary complications. Several clinical trials are currently underway for FSHD. New and emerging treatments focus on correcting the transcriptional misregulation of D4Z4 and reversing the cytotoxic effects of DUX4. Other potential therapeutic targets include reduction of inflammation, improving muscle mass, and activating compensatory molecular pathways. The utility of disease-modifying treatments will depend on selection of sensitive clinical endpoints as well as validation of muscle magnetic resonance imaging (MRI) and other biomarkers to detect meaningful changes in disease progression. Correction of the epigenetic defects using new gene editing as well as other DUX4 silencing technologies offers potential treatment options for many individuals with FSHD.

scholarly journals Inhibition ofDUX4expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy

2020 ◽  
Vol 117 (28) ◽  
pp. 16509-16515 ◽  
Author(s):  
Kenji Rowel Q. Lim ◽  
Rika Maruyama ◽  
Yusuke Echigoya ◽  
Quynh Nguyen ◽  
Aiping Zhang ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Messenger Rna ◽  
Screening Method ◽  
Local Treatment ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Locked Nucleic Acid ◽  
Aberrant Expression ◽  
Progressive Muscle Weakness

Facioscapulohumeral muscular dystrophy (FSHD), characterized by progressive muscle weakness and deterioration, is genetically linked to aberrant expression ofDUX4in muscle. DUX4, in its full-length form, is cytotoxic in nongermline tissues. Here, we designed locked nucleic acid (LNA) gapmer antisense oligonucleotides (AOs) to knock downDUX4in immortalized FSHD myoblasts and theFLExDUX4FSHD mouse model. Using a screening method capable of reliably evaluating the knockdown efficiency of LNA gapmers against endogenousDUX4messenger RNA in vitro, we demonstrate that several designed LNA gapmers selectively and effectively reducedDUX4expression with nearly complete knockdown. We also found potential functional benefits of AOs on muscle fusion and structure in vitro. Finally, we show that one of the LNA gapmers was taken up and induced effective silencing ofDUX4upon local treatment in vivo. The LNA gapmers developed here will help facilitate the development of FSHD therapies.

scholarly journals Associations between joint effusion in the knee and gene expression levels in the circulation: a meta-analysis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 109 ◽  
Author(s):  
Marjolein J. Peters ◽  
Yolande F.M. Ramos ◽  
Wouter den Hollander ◽  
Dieuwke Schiphof ◽  
Albert Hofman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Antigen Processing ◽  
Early Stage ◽  
Meta Analysis ◽  
Biological Pathways ◽  
Joint Effusion ◽  
Expression Levels ◽  
Cell Counts ◽  
Gene Expression Levels

Objective: To identify molecular biomarkers for early knee osteoarthritis (OA), we examined whether joint effusion in the knee associated with different gene expression levels in the circulation.Materials and Methods: Joint effusion grades measured with magnetic resonance (MR) imaging and gene expression levels in blood were determined in women of the Rotterdam Study (N=135) and GARP (N=98). Associations were examined using linear regression analyses, adjusted for age, fasting status, RNA quality, technical batch effects, blood cell counts, and BMI. To investigate enriched pathways and protein-protein interactions, we used the DAVID and STRING webtools.Results: In a meta-analysis, we identified 257 probes mapping to 189 unique genes in blood that were nominally significantly associated with joint effusion grades in the knee. Several compelling genes were identified such as C1orf38 and NFATC1. Significantly enriched biological pathways were: response to stress, gene expression, negative regulation of intracellular signal transduction, and antigen processing and presentation of exogenous pathways.Conclusion: Meta-analyses and subsequent enriched biological pathways resulted in interesting candidate genes associated with joint effusion that require further characterization. Associations were not transcriptome-wide significant most likely due to limited power. Additional studies are required to replicate our findings in more samples, which will greatly help in understanding the pathophysiology of OA and its relation to inflammation, and may result in biomarkers urgently needed to diagnose OA at an early stage.

The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy

2019 ◽  
Vol 20 (1) ◽  
pp. 265-291 ◽  
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.

scholarly journals Evaluation of blood gene expression levels in facioscapulohumeral muscular dystrophy patients

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
M. Signorelli ◽  
A. G. Mason ◽  
K. Mul ◽  
T. Evangelista ◽  
H. Mei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Clinical Performance ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Differentially Expressed ◽  
Patient Classification ◽  
Examine Gene Expression ◽  
Or Groups

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is caused by the expression of DUX4 in skeletal muscles. A number of therapeutic approaches are being developed to antagonize the events preceding and following DUX4 expression that leads to muscular dystrophy. Currently, the possibility to evaluate treatment response in clinical trials is hampered by the lack of objective molecular biomarkers connecting the disease cause to clinical performance. In this study we employed RNA-seq to examine gene expression in PAXgene tubes obtained from two independent cohorts of FSHD patients. Analysis of gene expression profiles did not lead to the identification of genes or pathways differentially expressed in FSHD patients, or associated with disease severity. In particular, we did not find evidence that the DUX4 and PAX7 signatures were differentially expressed. On the other hand, we were able to improve patient classification by including single genes or groups of genes in classification models. The best classifier was ROPN1L, a gene known to be expressed in testis, coincidentally the typical location of DUX4 expression. These improvements in patient classification hold the potential to enrich the FSHD clinical trial toolbox.

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