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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193710 | GEO | 2022/01/17

REPOSITORIES: GEO

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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

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

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes [DNA-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. However, it has been reported that after precise genome engineering human iPSCs may show severe alterations of the p53 gene. With the aim to evaluate the genome engeneering impact on the p53 pathway in the CRISPR-CAS9 knock out clones we verified integrity of the p53 genome sequence after gene editing.

2022-01-17 | GSE193712 | 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

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

Project description: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.

2015-07-17 | GSE57353 | GEO

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

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

Project description:DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes

| PRJNA797369 | ENA

Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

Project description:Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

| PRJEB27958 | ENA

Intrinsic self-DNA triggers inflammatory disease dependent on STING (I)

Project description:Inflammatory diseases such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE) are generally lethal disorders that have been traced to defects in the exonuclease Trex1 (DNAseIII). Mice lacking Trex1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the STING (stimulator of interferon genes) pathway. Here we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Trex1-/- macrophages did not exhibit significant augmented ability to produce pro-inflammatory cytokines compared to normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies. Total RNA obtained from wild type (WT), Trex1 deficient (TKO), STING deficient (SKO), or Trex1 and STING double deficient (STKO) mouse Heart

2014-07-09 | E-GEOD-59217 | biostudies-arrayexpress

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