Topoisomerase IIIb protects from immune dysregulation and tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA1245401 | ENA |
REPOSITORIES: ENA
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Project description:Topoisomerase IIIb protects from immune dysregulation and tumorigenesis
| PRJNA1245408 | ENA
Project description:Topoisomerase III-beta (Top3b) reduces nucleic acid torsional stress and intertwining generated during RNA and DNA metabolism while protecting the genome from pathological R-loops, which otherwise result in DNA breakage and genome instability. By studying Top3b knockout mice (Top3b-KO), we find that the loss of Top3b accelerates the development of spontaneous atypical lymphoid hyperplasia and lymphomas arising in spleens and lymph nodes, the organs with prominent Top3b expression. Aging Top3b-KO mice also display splenomegaly and systemic immune alterations including neutrophilia and lymphopenia consistent with chronic inflammation. At the molecular level, Top3b deficiency causes genome-wide R-loop accumulation in splenocytes as measured by CUT&Tag sequencing. Increased R-loops are associated with genomic breaks and activation of immune signaling pathways including innate and adaptive immune cell signaling, IL-4 signaling, FAK signaling and cGAS-STING. Additionally, knocking-out Top3b promotes the rapid development of syngeneic EL4 T-cell lymphomas. In conclusion, our work suggests that Top3b protects from lymphoma, tumorigenesis and immune dysregulations.
2025-09-05 | GSE293640 | GEO
Project description:Topoisomerase III-beta (Top3b) reduces nucleic acid torsional stress and intertwining generated during RNA and DNA metabolism while protecting the genome from pathological R-loops, which otherwise result in DNA breakage and genome instability. By studying Top3b knockout mice (Top3b-KO), we find that the loss of Top3b accelerates the development of spontaneous atypical lymphoid hyperplasia and lymphomas arising in spleens and lymph nodes, the organs with prominent Top3b expression. Aging Top3b-KO mice also display splenomegaly and systemic immune alterations including neutrophilia and lymphopenia consistent with chronic inflammation. At the molecular level, Top3b deficiency causes genome-wide R-loop accumulation in splenocytes as measured by CUT&Tag sequencing. Increased R-loops are associated with genomic breaks and activation of immune signaling pathways including innate and adaptive immune cell signaling, IL-4 signaling, FAK signaling and cGAS-STING. Additionally, knocking-out Top3b promotes the rapid development of syngeneic EL4 T-cell lymphomas. In conclusion, our work suggests that Top3b protects from lymphoma, tumorigenesis and immune dysregulations.
2025-09-05 | GSE293641 | GEO
Project description:Mucopolysaccharidosis IIIB (MPS IIIB) is a rare genetic disorder caused by defects in α-N-acetylglucosaminidase, which breaks down extracellular heparan sulfate. Symptoms progress from hyperactivity and sleep disruptions during childhood to severe neurodegeneration during adolescence. To generate an MPS IIIB model in the fruitfly, Drosophila melanogaster, we introduced mutations in the corresponding fly enzyme that correlate with patient mutations. The fly model recapitulates sleep fragmentation and hyperactivity observed in patients and enlarged lysosomes in the brain. Genes associated with synaptic function and neurodevelopment showed altered expression in the brain. The Drosophila model can enable future development of therapies for MPS IIIB.
2025-03-26 | GSE269032 | GEO
Project description:Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegradedheparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. To identify potential biomarkers and novel neuropathological mechanisms of MPS IIIB, a label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses of the differentially abundant proteins allowed to define three major clusters: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The results highlight the involvement of these clustered proteins in the neuropathology of MPS IIIB disease. The proteins identified in this study would provide potential targets for diagnostic and therapeutic studies of MPS IIIB.
2020-02-26 | PXD017363 | Pride
Project description:Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation
| PRJNA318003 | ENA
Project description:A Drosophila model of mucopolysaccharidosis IIIB
| PRJNA1119989 | ENA
Project description:The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of numerous diseases associated with exacerbated inflammation. Here, we identify Topoisomerase 1 (Top1) as a critical positive regulator of RNA polymerase II (RNAPII) transcriptional activity at pathogen-induced genes. Notably, depletion or chemical inhibition of Top1 suppresses the host response against replicating Influenza and Ebola viruses as well as bacterial products. As a result, therapeutic pharmacological inhibition of Top1 protects mice from death in experimental models of chemical- and pathogen-induced lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life threatening infections characterized by an acutely exacerbated immune response.
2016-07-11 | GSE80131 | GEO
Project description:The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of numerous diseases associated with exacerbated inflammation. Here, we identify Topoisomerase 1 (Top1) as a critical positive regulator of RNA polymerase II (RNAPII) transcriptional activity at pathogen-induced genes. Notably, depletion or chemical inhibition of Top1 suppresses the host response against replicating Influenza and Ebola viruses as well as bacterial products. As a result, therapeutic pharmacological inhibition of Top1 protects mice from death in experimental models of chemical- and pathogen-induced lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life threatening infections characterized by an acutely exacerbated immune response.
2016-07-11 | GSE80129 | GEO
Project description:PIGA mutation and glycosylphosphatidylinositol anchor dysregulation in polyposis-associated duodenal tumorigenesis
| PRJNA781233 | ENA