| 1. |
- Pan, Lang, et al.
(författare)
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8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury
- 2023
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 51:3, s. 1087-1102
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Tidskriftsartikel (refereegranskat)abstract
- Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.
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| 2. |
- Pan, Lang, et al.
(författare)
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Substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) reprograms mucosal adaptations to chronic airway injury
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Recent advances have uncovered the non-random distribution of 7, 8-dihydro-8-oxoguanine (8-oxoGua) induced by reactive oxygen species, which is believed to have epigenetic effects. Its cognate repair protein, 8-oxoguanine DNA glycosylase 1 (OGG1), reads oxidative substrates and participates in transcriptional initiation. When redox signaling is activated in small airway epithelial cells, the DNA repair function of OGG1 is repurposed to transmit acute inflammatory signals accompanied by cell state transitions and modification of the extracellular matrix. Epithelial-mesenchymal and epithelial-immune interactions act cooperatively to establish a local niche that instructs the mucosal immune landscape. If the transitional cell state governed by OGG1 remains responsive to inflammatory mediators instead of differentiation, the collateral damage provides positive feedback to inflammation, ascribing inflammatory remodeling to one of the drivers in chronic pathologies. In this review, we discuss the substrate-specific read through OGG1 has evolved in regulating the innate immune response, controlling adaptations of the airway to environmental and inflammatory injury, with a focus on the reader function of OGG1 in initiation and progression of epithelial to mesenchymal transitions in chronic pulmonary disease.
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| 3. |
- Tanner, Lloyd, et al.
(författare)
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Pharmacological OGG1 inhibition decreases murine allergic airway inflammation
- 2022
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lymphoid cells, type 2 T helper cells, macrophages, and eosinophils. The disease is characterized by wheezing, dyspnea, coughing, chest tightness and variable airflow limitation for which there is no cure and is symptomatically treated with inhaled corticosteroids and β2-agonists. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammation.Methods: Using a murine ovalbumin (OVA) model of allergic airway inflammation we assessed the utility of an inhibitor of OGG1 (TH5487) in this disease context. Cytokines and chemokines, promoting immune cell recruitment were measured using a 23-multiplex assay and Western blotting. Additionally, immune cell recruitment to bronchi was measured using flow cytometry. Histological analyses and immunofluorescent staining were used to confirm immune cell influx and goblet cell hyperplasia of the airways. A PCR array was used to assess asthma-related genes in murine lung tissue following TH5487 treatment. Finally, airway hyperresponsiveness was determined using in vivo lung function measurement.Results: In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-κB and expression of proinflammatory cytokines and chemokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed differences in several important regulators, including down regulation of Tnfrsf4, Arg1, Ccl12 and Ccl11, and upregulation of the negative regulator of type 2 inflammation, Bcl6. Furthermore, the gene Clca1 was upregulated following TH5487 treatment, which should be explored further due to its ambiguous role in allergic asthma. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment.Conclusion: Taken together, the data presented in this study suggest OGG1 as a clinically relevant pharmacological target for the treatment of allergic inflammation.
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| 4. |
- Xue, Yaoyao, et al.
(författare)
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Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression. We found that functional inhibition, genetic ablation, and inactivation by post-translational modification of OGG1 significantly augment IFN-λ expression in epithelial cells infected by human respiratory syncytial virus (RSV). Mechanistically, OGG1 bound to 8-oxoGua in proximity to interferon response elements, which inhibits the IRF3/IRF7 and NF-κB/RelA DNA occupancy, while promoting the suppressor NF-κB1/p50-p50 homodimer binding to the IFN-λ2/3 promoter. In a mouse model of bronchiolitis induced by RSV infection, functional ablation of OGG1 by a small molecule inhibitor (TH5487) enhances IFN-λ production, decreases immunopathology, neutrophilia, and confers antiviral protection. These findings suggest that the ROS-generated epigenetic mark 8-oxoGua via its reader OGG1 serves as a homeostatic thresholding factor in IFN-λ expression. Pharmaceutical targeting of OGG1 activity may have clinical utility in modulating antiviral response.
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