Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutières syndrome

ABSTRACT: Aicardi-Goutières syndrome (AGS) is a severe childhood inflammatory disorder that shows clinical and genetic overlap with systemic lupus erythematosus (SLE). AGS is thought to arise from the accumulation of incompletely metabolized endogenous nucleic acid species owing to mutations in nucleic acid degrading enzymes TREX1 (AGS1), RNase H2 (AGS2, 3 and 4) and SAMHD1 (AGS5). However, the identity and source of such immunogenic nucleic acid species remain undefined. Using genome-wide approaches, we show that fibroblasts from AGS patients with AGS1-5 mutations are burdened by excessive loads of RNA:DNA hybrids. Using MethylC-seq, we show that AGS fibroblasts display pronounced and global loss of DNA methylation and demonstrate that AGS-specific RNA:DNA hybrids often occur within DNA hypomethylated regions. Altogether, our data suggest that RNA:DNA hybrids may represent a common immunogenic form of nucleic acids in AGS and provide the first evidence of epigenetic perturbations in AGS, furthering the links between AGS and SLE.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57353 | GEO | 2015/07/17

SECONDARY ACCESSION(S): PRJNA246322

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

Project description:Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous encephalopathy whose pathology is linked to an abnormal type I interferon response induced by self-derived nucleic acids. Data indicate that endogenous retroelements represent one source of interferon-stimulatory self-nucleic acid. No effective therapies are available for this disorder. In this pilot study involving patients with AGS due to mutations in TREX1, RNASEH2A, RNASEH2B or SAMHD1 three nucleoside analogue reverse transcriptase inhibitors (RTIs) were administered over 12 months. Transcription profiling was done by RNA-seq.

2018-12-12 | E-MTAB-7087 | biostudies-arrayexpress

RNase H2, mutated in Aicardi‐Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation.

Project description:RNase H2 is a specialized enzyme that degrades RNA in RNA/DNA hybrids and deficiency of this enzyme causes a severe neuroinflammatory disease, Aicardi Goutières syndrome (AGS). However, the molecular mechanism underlying AGS is still unclear. Here, we show that RNase H2 is associated with a subset of genes, in a transcription-dependent manner where it interacts with RNA Polymerase II. RNase H2 depletion impairs transcription leading to accumulation of R-loops, structures that comprise RNA/DNA hybrids and a displaced DNA strand, mainly associated with short and intronless genes. Importantly, accumulated R-loops are processed by XPG and XPF endonucleases which leads to DNA damage and activation of the immune response, features associated with AGS. Consequently, we uncover a key role for RNase H2 in the transcription of human genes by maintaining R-loop homeostasis. Our results provide insight into the mechanistic contribution of R-loops to AGS pathogenesis.

2022-02-04 | GSE146970 | GEO

Altered DNA Methylation and Gene expression predict Disease Severity in Patients with Aicardi-Goutières Syndrome

Project description:Aicardi-Goutières Syndrome (AGS) is a rare neuro-inflammatory disease characterized by increased expression of interferon-stimulated genes (ISGs). Disease-causing mutations are present in genes associated with innate antiviral responses. Disease presentation and severity vary, even between patients with identical mutations from the same family. This study investigated DNA methylation signatures in PBMCs to understand phenotypic heterogeneity in AGS patients with mutations in RNASEH2B. AGS patients presented hypomethylation of ISGs and differential methylation patterns (DMPs) in genes involved in “neutrophil and platelet activation”. Patients with “mild” phenotypes exhibited DMPs in genes involved in “DNA damage and repair”, whereas patients with “severe” phenotypes had DMPs in “cell fate commitment” and “organ development” associated genes. DMPs in two ISGs (IFI44L, RSAD2) associated with increased gene expression in patients with “severe” when compared to “mild” phenotypes. In conclusion, altered DNA methylation and ISG expression as biomarkers and potential future treatment targets in AGS. This project aimed at testing the hypothesis that DNA methylation may influence gene expression, thereby affecting associated clinical phenotypes in AGS patients with the same mutation (RNASEH2B p.A177T).

2023-04-18 | GSE221644 | GEO

Ribonucleotides embedded in genomic DNA of Aicardi-Goutières syndrome (AGS)-orthologous mutants of Saccharomyces cerevisiae using ribose-seq protocol

Project description:Ribonucleoside monophosphates (rNMPs) are abundantly found in DNA of cells, with over a million counts in the mammalian genome and thousands in budding yeast DNA. The embedded rNMPs alter DNA properties, increasing DNA fragility and mutability. Mutations in any of the three subunits of ribonuclease (RNase) H2, a key enzyme for rNMP removal, are associated with the Aicardi-Goutières syndrome (AGS), a severe neurological disorder. Here, we engineered two AGS orthologous mutations in Saccharomyces cerevisiae: rnh201-G42S and rnh203-K46W. Using the ribose-seq technique and the Ribose-Map bioinformatics tool, we studied the rNMP incorporation frequency, distribution, composition, and patterns in these yeast mutants. We found significantly more abundant rNMPs in the nuclear genome of rnh201-G42S than in wild-type and rnh203-K46W-mutant cells. Moreover, we observed distinct sequence contexts and genomic sites with abundant rNMP incorporation (hotspots) in rnh201-G42S and rnh203-K46W cells, anticipating similar rNMP patterns in human DNA carrying the orthologous AGS mutations.

2023-12-25 | GSE240399 | GEO

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes [scRNA-Seq]

Project description:The contribution of the different CNS cell types to Aicardi-Goutiéres Syndrome pathogenesis is still unclear. With the aim to elucidate how oligodendrocytes, neurons and astrocytes impact AGS human phenotype we interrogate transcriptomes of the different cell populations performing single-cell RNA-Seq (scRNASeq). We compared cells deriving from AGS patient-derived iPSC harboring mutations in TREX1 (AGS1) or RNASEH2B (AGS2) to healthy donor control (WT) cells differentiated into mixed neuronal/glial cell populations.

2022-01-17 | GSE193710 | GEO

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes [RNA-Seq]

Project description:We generated iPS cells knock out (KO) for two Aicardi Goutières syndrome genes, TREX1 and RNASEH2b to model the disease in a human neurological context. Their transcriptomes were analyzed at several differentiation stages: iPSC-derived Neural Stem Cells, iPSC-derived proinflammatory astrocytes and iPSC-derived neurons. We then evaluated when and to which extent the AGS-related transcriptional alterations arised in all KO and WT cells.

2022-01-17 | GSE193711 | GEO

SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA

Project description:Recognition of pathogen-derived foreign nucleic acids is central to innate immune defense. This requires discrimination between structurally highly similar self and nonself nucleic acids to avoid aberrant inflammatory responses as in the autoinflammatory disorder Aicardi-Goutires syndrome (AGS). How vast amounts of self RNA are shielded from immune recognition to prevent autoinflammation is not fully understood. Here we show that SAM domain and HD domain-containing protein 1 (SAMHD1), one of the AGS-causing genes, functions as a single-stranded RNA (ssRNA) 3«exonuclease, the lack of which causes cellular RNA accumulation. Increased ssRNA in cells leads to dissolution of RNA-protein condensates, which sequester immunogenic double-stranded RNA (dsRNA). Release of sequestered dsRNA from condensates triggers activation of antiviral type I interferon via retinoic acid-inducible gene I-like receptors. Our results establish SAMHD1 as a key regulator of cellular RNA homeostasis and demonstrate that buffering of immunogenic self RNA by condensates regulates innate immune responses.

2023-02-06 | PXD035182 | Pride

cytoDRIP-seq in HeLa cells

Project description:R-loops are three-stranded nucleic acid structures that have important regulatory roles in cells. Deregulation of R-loop dynamics, however, can lead to DNA damage and genome instability, which results from the action of endonucleases such as XPG on R-loops. The mechanism by which this R-loop processing occurs and the impact on the cell remain unclear. Here, we show that cells with R-loops induced by deregulation of the RNA-DNA helicase Senataxin (SETX), the breast cancer gene BRCA1, or RNA splicing, accumulate cytoplasmic RNA-DNA hybrids in an XPG-dependent manner. Sequencing of cytoplasmic hybrids upon loss of SETX shows that they are derived from a subset of nuclear RNA-DNA hybrids that have longer lifetimes, signal on both sense and antisense strands and contain regions with switches in nucleotide skew. We further show that induced cytoplasmic hybrids bind the pattern recognition receptors cGAS and TLR3, activating IRF3 and inducing apoptosis. Ataxia oculomotor apraxia type 2 (AOA2) patient cells which harbor a mutated SETX also exhibit XPG-dependent activation of the innate immune response. These findings identify RNA-DNA hybrids as novel, immunogenic nucleic acid species which aberrantly accumulate in the cytoplasm of cells upon R-loop processing, and can ultimately induce cell apoptosis. We anticipate that aberrant R-loop processing and subsequent innate immune activation may be a pathological process that contributes to many disease states, such as neurodegeneration and cancer.

2022-10-26 | GSE178841 | GEO

RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships (RNA-seq)

Project description:Mapping of RNA:DNA hybrids in human cells reveals a number of characteristics of these non-canonical nucleic acid structures. A directional sequencing approach reveals the RNA component of the RNA:DNA hybrid to be purine-rich, indicating a thermodynamic contribution to the stability of these structures. The RNA:DNA hybrids are enriched at loci with decreased DNA methylation and increased DNase hypersensitivity, and within larger domains with characteristics of heterochromatin formation. Studies of chromatin at RNA:DNA hybrids shows the presence of the ILF2 and ILF3 transcription factors, supporting a model of certain transcription factors binding preferentially to the RNA:DNA conformation. Overall, there is little to indicate a dependence for RNA:DNA hybrids forming co-transcriptionally, with results from the ribosomal DNA repeat unit instead supporting a model of RNA generating these structures in trans. The results of the study indicate heterogeneous functions of these genomic elements and new insights into their formation and stability in vivo.

2015-06-15 | GSE68938 | GEO

RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships RDIP-seq)

2015-06-15 | GSE68948 | GEO