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Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy

ABSTRACT: Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy

PROVIDER: PRJNA828606 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18841147_1.fastq.gz	Fastqsanger.gz
	SRR18841147_2.fastq.gz	Fastqsanger.gz
	SRR18841148_1.fastq.gz	Fastqsanger.gz
	SRR18841148_2.fastq.gz	Fastqsanger.gz
	SRR18841149_1.fastq.gz	Fastqsanger.gz

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Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy [RNA-seq]

Project description:Facioscapulohumeral muscular dystrophy (FSHD), a progressive skeletal muscle disorder, is epigenetically characterized with DNA hypomethylation of D4Z4 repeats in 4q35 region, allowing aberrant DUX4 expression. Sustainable DUX4 suppression is a promising therapeutic clue to prevent disease progression, but most of the supposed methods depend on expression of their mediator biochemical entity, potentially narrowing QoL of individuals with FSHD in the clinical context. In this study, we report that by applying hit-and-run silencing with dCas9-mediated epigenetic editing targeting DNA hypomethylation on D4Z4 repeats, we could achieve suppression of endogenous DUX4 in our FSHD patients-derived iPSC model. Notably, DNA methylation was significantly upregulated in FSHD cells and suppression effect was observed at least two weeks after intervention, which was not the case by transient treatment of typical dCas9-KRAB alone. Off-target analysis showed that despite the potential genome-wide risk in DNA methylation, the impact on transcriptome was limited. We propose that hit-and-run silencing can be a promising option to prevent disease progression with minimum intervention for individuals with FSHD, motivating further study for clinical development.

2024-03-31 | GSE201178 | GEO

Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy [EPIC Methylation]

2024-03-31 | GSE199690 | GEO

Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy [EPIC Methylation]

Project description:Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy [EPIC Methylation]

| PRJNA821190 | ENA

Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy [RNA-seq]

Project description:Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy [RNA-seq]

| PRJNA828600 | ENA

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

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

A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.

Project description:Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor, which is mutated in >95% of Facioscapulohumeral dystrophy (FSHD) type 2 cases. In FSHD2, SMCHD1 mutations ultimately result in the presence of the cleavage stage transcription factor DUX4 in muscle cells due to a failure in epigenetic repression of the D4Z4 macrosatellite repeat on chromosome 4q, which contains the DUX4 locus. While binding of SMCHD1 to D4Z4 and its necessity to maintain a repressive D4Z4 chromatin structure are well documented, it is unclear how SMCHD1 is recruited to D4Z4, and how it exerts its repressive properties on the chromatin. Here, we employ a quantitative proteomics approach to identify and characterize novel SMCHD1 interacting proteins, and assess their functionality in D4Z4 repression. We identify 47 robust SMCHD1 interactors, of which 19 are present in D4Z4 chromatin. We demonstrate that one of these SMCHD1 interacting proteins in D4Z4, RuvB-like 1 (RUVBL1) is indeed required for maintaining DUX4 silencing in FSHD myocytes. We also confirm the interaction of SMCHD1 with EZH inhibitory protein (EZHIP), which prevents global H3K27me3 deposition by the Polycomb repressive complex PRC2, providing novel insights into the potential function of SMCHD1 in the repression of DUX4 in the early stages of embryogenesis. The SMCHD1 interactome outlined herein can thus provide further direction into research on the potential function of SMCHD1 at genomic loci where SMCHD1 is known to act, such as D4Z4 repeats, the inactive X chromosome, autosomal gene clusters, imprinted loci and telomeres.

2021-12-15 | PXD023993 | Pride

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

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

DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle

Project description:Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of yet unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration. RNA-seq for muscle cells and biopsies from control and FSHD individuals.

2014-07-03 | E-GEOD-56787 | biostudies-arrayexpress

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

2012-01-03 | GSE33838 | GEO

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

2012-01-03 | GSE33799 | GEO