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

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

PROVIDER: PRJNA612527 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11305700_1.fastq.gz	Fastqsanger.gz
	SRR11305700_2.fastq.gz	Fastqsanger.gz
	SRR11305701_1.fastq.gz	Fastqsanger.gz
	SRR11305701_2.fastq.gz	Fastqsanger.gz
	SRR11305681_1.fastq.gz	Fastqsanger.gz

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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.

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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.

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Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

Project description:Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

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Bulk RNAseq of post-mortem brain tissue of Aicardi-Goutières Syndrome patients and non-diseased controls

Project description:Post mortem brain tissue of three Patients suffering from Aicardi-Goutières Syndrome from different brain regions was used to isolate RNA and perform RNAseq analysis compared to age matched control patients with no underlying brain pathology.

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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.

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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.

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

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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.

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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.

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

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

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