DUX4-induced transcripts from pericentric human satellite II repeats form double-stranded RNA [dsRIPseq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA473170 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7221310.fastq.gz | Fastqsanger.gz | |||
| SRR7221320.fastq.gz | Fastqsanger.gz | |||
| SRR7221311.fastq.gz | Fastqsanger.gz | |||
| SRR7221321.fastq.gz | Fastqsanger.gz | |||
| SRR7221312.fastq.gz | Fastqsanger.gz |
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Project description:The DUX4 transcription factor is normally expressed in the cleavage stage embryo and regulates genes involved in zygotic genome activation. Mis-expression of DUX4 in skeletal muscle, however, is toxic and causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity is due, in part, to the accumulation of double-stranded RNAs (dsRNAs) with concomitant activation of the PKR viral response pathway. Here, using dsRNA immunoprecipitation coupled with next-generation sequencing, we determined that DUX4-induced dsRNAs originate from intergenic regions enriched for Alu and LINE-1 elements, endogenous retroviruses, and pericentric human satellite II (HSATII) repeats. DUX4-induced HSATII dsRNAs are formed via temporally controlled bidirectional expression with predominant transcription of one strand preceding the other. Whereas DUX4 activation of dsRNAs derived from intergenic regions such as HSATII contributes to toxicity in FSHD, in the early embryo these dsRNAs might facilitate heterochromatin formation, as has been proposed for cleavage stage expression of mouse major satellites.
2019-10-30 | GSE114938 | GEO
Project description:The DUX4 transcription factor is normally expressed in the cleavage stage embryo and regulates genes involved in zygotic genome activation. Mis-expression of DUX4 in skeletal muscle, however, is toxic and causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity is due, in part, to the accumulation of double-stranded RNAs (dsRNAs) with concomitant activation of the PKR viral response pathway. Here, using dsRNA immunoprecipitation coupled with next-generation sequencing, we determined that DUX4-induced dsRNAs originate from intergenic regions enriched for Alu and LINE-1 elements, endogenous retroviruses, and pericentric human satellite II (HSATII) repeats. DUX4-induced HSATII dsRNAs are formed via temporally controlled bidirectional expression with predominant transcription of one strand preceding the other. Whereas DUX4 activation of dsRNAs derived from intergenic regions such as HSATII contributes to toxicity in FSHD, in the early embryo these dsRNAs might facilitate heterochromatin formation, as has been proposed for cleavage stage expression of mouse major satellites.
2019-10-30 | GSE114936 | GEO
Project description:DUX4-induced transcripts from pericentric human satellite II repeats form double-stranded RNA [stranded-RNAseq]
| PRJNA473169 | ENA
Project description:DUX4-induced transcripts from pericentric human satellite II repeats form double-stranded RNA
| PRJNA473167 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-10-30 | GSE114940 | GEO
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 | GSE199690 | GEO
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
Project description:The DUX4 transcription factor is normally expressed in the cleavage-stage embryo and regulates genes involved in embryonic genome activation. Misexpression of DUX4 in skeletal muscle, however, is toxic and causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity is due, in part, to the activation of the double-stranded RNA (dsRNA) response pathway and the accumulation of intranuclear dsRNA foci. Here, we determined the composition of DUX4-induced dsRNAs. We found that a subset of DUX4-induced dsRNAs originate from inverted Alu repeats embedded within the introns of DUX4-induced transcripts and from DUX4-induced dsRNA-forming intergenic transcripts enriched for endogenous retroviruses, Alu and LINE-1 elements. However, these repeat classes were also represented in dsRNAs from cells not expressing DUX4. In contrast, pericentric human satellite II (HSATII) repeats formed a class of dsRNA specific to the DUX4 expressing cells. Further investigation revealed that DUX4 can initiate the bidirectional transcription of normally heterochromatin-silenced HSATII repeats. DUX4-induced HSATII RNAs co-localized with DUX4-induced nuclear dsRNA foci and with intranuclear aggregation of EIF4A3 and ADAR1. Finally, gapmer-mediated knockdown of HSATII transcripts depleted DUX4-induced intranuclear ribonucleoprotein aggregates and decreased DUX4-induced cell death, suggesting that HSATII-formed dsRNAs contribute to DUX4 toxicity.
| S-EPMC7342170 | biostudies-literature
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:DUX4 is a double homeodomain transcription factor whose misexpression in the muscle causes facioscapulohumeral muscular dystrophy (FSHD). The transcriptional activity of DUX4 has been extensively characterized, and is thought to be the primary driver of FSHD pathogenesis. Yet, DUX4 expression lowers the protein level of an RNA quality control factor, UPF1, without affecting its transcript level, hinting at post-transcriptional regulatory activity downstream of DUX4 expression. How extensive the post-transcriptional activity of DUX4 is, and how relevant it is to FSHD pathogenesis, is unknown. In order to gain insight into DUX4-induced post-transcriptional gene regulation, we measured transcript and protein levels in DUX4 expressing cells via RNA-seq and SILAC-based quantitative mass spectrometry, respectively. We show that DUX4 transcriptional targets are robustly translated, including those genes previously identified as potential FSHD biomarkers. However, comparing the overall pattern of gene expression changes for RNA versus protein reveals striking differences in the most highly activated pathways, with the former showing changes in RNA processing and splicing, and the latter affecting the humoral immune response, proteolysis and exocytosis, among other pathways. Consistent with a misregulation of exocytosis, fluorescence imaging shows fragmented golgi apparatus in DUX4-expressing cells. Of the genes that showed discordant RNA and protein expression levels, post-transcriptional buffering was particularly evident for genes involved in stress response and may explain why DUX4-expressing cells succumb to toxicity despite robust transcriptional activation of stress response genes. Moreover, several genes involved in RNA decay including UPF1, UPF3B, SMG6 and XRN1 showed downregulation at the protein level, which may explain the massive inhibition of RNA quality control in DUX4-expressing cells. These results highlight the importance of considering post-transcriptional gene regulation in DUX4-expressing cells in order to fully understand the FSHD disease process.
2019-01-21 | PXD010221 | Pride