RNA Expression of TH10785 treated human T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE309061 | GEO | 2025/09/29
REPOSITORIES: GEO
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Project description:To study whether increase in mitochondrial oxidative stress (SOD2 removal) and decrease in mitochondrial DNA repair (Ogg1 dMTS) results into increase in mutations in mitochondrial RNA (mtRNA). Oxidative stress has been suggested to induce mutations in mtDNA and as DNA is used as a template in transcription, mutations or 8-oxo-dG on DNA can induce GC>TA transversion accumulation in mtRNA. To verify this, we extracted and sequenced (Illumina) total RNA from heart Sod2 knockout mice alone and mice that were also deficient for mitochondrial base-excision repair. The repair deficiency was induced by removing the genomic region encoding for the predicted mitochondrial targeting sequence from endogenous OGG1 (L2 to W23) called Ogg1 dMTS mice, thus excluding the protein from mitochondria. OGG1 is a DNA glycosylase that recognizes and repairs 8-oxo-dG damage from DNA. Oxidative stress can induce 8-oxo-dG lesions, thus we removed the mitochondrial matrix localized superoxide dismutase (SOD2) from these mice to increase the level of oxidative stress. 8-oxo-dG lesion can be mutagenic because some DNA repair polymerases are known to erroneously incorporate adenosine opposite to 8-oxo-dG during replication leading to GC>TA transversion mutations.
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Project description:Base excision repair initiated by DNA glycosylases is known to preserve genomic integrity by removing damaged bases. Besides, DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome associated with cognition but independent of DNA damage repair. However, the underlying molecular mechanisms are not fully understood. Here, we combine transcriptomic and epigenomic analyses of the hippocampus in mice deficient in DNA glycosylases. We report that the combined deficiency of Ogg1 and Mutyh impairs spatial but not associative long-term memory. Mechanistically, Ogg1 and Mutyh modulate DNA methylation of polycomb repressive complex 2 (PRC2) target genes. We find that the occupancy of PRC2 and histone modifications associated with PRC2 activity depend on Ogg1 and Mutyh in neurons and glia. These epigenetic changes correlate with cell-type specificdifferences in gene expression of PRC2 targets. Our results uncover a novel role for Ogg1 and Mutyh beyond DNA repair in modulating the epigenome to control transcriptional responses in the brain important for memory formation.
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Project description:Respiratory Syncytial Virus (RSV), alongside other prominent respiratory RNA viruses such as influenza and SARS-CoV-2, significantly contributes to the global incidence of respiratory tract infections. These pathogens prompt the production of reactive oxygen species (ROS), which play a crucial role in the onset and progression of respiratory diseases. However, the strategies by which viral RNA manages ROS-induced base oxidation are not well understood. Here we uncover that 8-oxo-7,8-dihydroguanine (8-oxoGua) is not merely an incidental byproduct of ROS activity but serves as a strategic adaptation of RSV RNA during replication within host cells. Through RNA immunoprecipitation and next-generation sequencing, we discovered that 8-oxoguanine DNA glycosylase 1 (OGG1) binding sites are predominantly found in the RSV antigenome, especially within guanine-rich areas. Further investigation revealed that viral ribonucleoprotein complexes specifically hijack OGG1. Crucially, our findings show that inhibiting OGG1's ability to recognize 8-oxoGua leads to a substantial reduction in RSV progeny production. Our results underscore the viral replication machinery's adaptation to oxidative challenges, pointing to the inhibition of OGG1's reading function as a potential novel strategy for antiviral intervention.
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