HDAC1 modulates OGG1-initiated oxidative DNA damage repair, brain aging, and Alzheimer’s disease pathology
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PROVIDER: PRJNA474958 | ENA |
REPOSITORIES: ENA
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Project description:Unrepaired DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair activity to stave off age-associated functional decline remain obscure. Here, we show that histone deacetylase 1 (HDAC1) modulates DNA repair in the aging brain via targeting OGG1 of the base excision repair pathway. Mice deficient in HDAC1 display age-associated accumulation of DNA damage in the brain and cognitive impairment. HDAC1 interacts with and positively stimulates OGG1, a DNA glycosylase that primarily acts on 8-oxoguanine (8-oxoG), a type of oxidative DNA damage associated with transcriptional repression. Loss of HDAC1 leads to impaired OGG1 activity, 8-oxoG accumulation at the promoters of a subset of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG lesions along with reduced HDAC1 activity and downregulation of a similar set genes in the 5XFAD mouse model of Alzheimer’s disease (AD). Notably, pharmacological activation of HDAC1 confers protection against the deleterious effects of 8-oxoG lesions in the brains of aged wild-type and 5XFAD mice. Our work uncovers an important role for HDAC1 in the repair of 8-oxoG lesions and highlights HDAC1 activation as a novel therapeutic strategy to counter functional decline during brain aging and neurodegeneration.
2020-03-30 | GSE115437 | GEO
Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.
2023-02-06 | PXD029625 | Pride
Project description:Gene expression in livers of male wild-type (WT) and OGG1-deficient (Ogg1-/-) mice fed either a chow diet or a high-fat diet (HFD) were examined. Mice were fed the diet for 10 weeks prior to tissue collection and were 22 weeks of age at the time of tissue collection. 24 Total samples were analyzed. We generated the following pairwise comparisons using GeneSifter: WT Chow vs Ogg1-/- Chow; WT HFD vs. Ogg1-/- HFD using t-test followed by Benjamini and Hochberg correction. An adjusted p-value less than 0.05 was considered to be statistically significant.
2012-12-16 | E-GEOD-35497 | biostudies-arrayexpress
Project description:Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology
| PRJNA674866 | ENA
Project description: Not available
| S-EPMC7235043 | biostudies-literature
Project description:Gene expression in livers of male wild-type (WT) and OGG1-deficient (Ogg1-/-) mice fed either a chow diet or a high-fat diet (HFD) were examined. Mice were fed the diet for 10 weeks prior to tissue collection and were 22 weeks of age at the time of tissue collection.
2012-12-16 | GSE35497 | GEO
Project description:Purpose: The aim of this study is to evaluate the global gene expression induced by OGG1-BER product 8-oxoG in mouse airways. Methods: RNA extracted from individual mouse lungs (experimental group: n=5) were pooled and a total 1 μg RNA was used for Next-Generation Sequencing (NGS) analyses on an Illumina HiSeq 1000 sequencing system. Sequence analysis were performed in duplicate. First- and second-strand synthesis, adapter ligation and amplification of the library were performed using the Illumina TruSeq Sample Preparation Kit as recommended by the manufacturer (Illumina). Library quality was evaluated by using an Agilent DNA-1000 chip on an Agilent 2100 Bioanalyzer. Library DNA templates were quantitated by qPCR using known reference starndards. Cluster formation of the library of DNA templates was performed using the TruSeq PE Cluster Kit v3 (Illumina) and the Illumina cBot workstation. Paired-end, 50-base sequencing was performed with a TruSeq SBS kit v3 (Illumina) on the Illumina HiSeq 1000 by protocols defined by the manufacturer. Base call conversion to sequence reads was performed using CASAVA-1.8.2. Sequence data were analyzed with the Bowtie2, Tophat2 and GFOLD programs. Processed data are presented as reads per kilobase transcript per million (RPKM), normalized to the experimental control (RNA from saline-challenged lungs) and reported as fold change (test/control). Results: We mapped an average of 24.76 million sequence reads per sample and identified 23,337 transcripts in total RNA extracted from lungs of Balb/cJ mice as described in Methods. Approximately 10% of the transcripts showed differential expression between the saline-challenged control and 8-oxoguanine-challeged mouse lungs, with a fold change ≥3.0. We validated the expression changes of 7 selected pro-inflammatory cytokines and chemokines of interest for our studies by qRT-PCR. Hierarchical clustering followed by Protein ANalysis THrough Evolutionary Relationships database (PANTHER) analysis of differentially expressed genes. Results showed overrepresentation of various biological functions (GO terms) including immune system process (GO:0002376; p=5.24e-12) among others. Pathway analysis (PANTHER) indicated that the most overrepresented pathway was inflammation mediated by chemokine and cytokine (P00031, p=<0.01). In addition to gene expression analysis, we confirmed OGG1•8-oxoG-dependent RAS activation in lungs by active RAS pull-down assays, airways neutrophil accumulation by bronchoalveolar lavage fluid (BALF) differential cell counts and airway inflammation by histological examination (H&E staining) of lung sections. Conclusions: This is the first study at the whole-transcriptome level to show induction of innate immune response gene expression in mouse lungs after exposure to OGG1-BER product 8-oxoG.
2015-02-02 | GSE61095 | GEO
Project description:To investigate the role of 8-oxo-7, 8-dihydroguanine (8-oxoguanine) accumulation in DNA or nucleotide pools during the development of AD pathology, we introduced a Mth1/Ogg1-double deficiency into homozygous triple-transgenic AD model (3xTg-AD-H) mice. Mth1 encodes 8-oxo-7, 8-dihydro-2'-deoxyguanosine-5'-triphosphatase (8-oxo-dGTPase) and Ogg1 encodes 8-oxoguanine DNA glycosylase 1. One-way eBays ANOVA of microarray data from hippocampi revealed that the gene expression profiles are most significantly altered in the hippocampi of 3xTg-AD-H with Mth1/Ogg1-double deficient (ADH/TO-DKH) mice compared to non-Tg control (NT) mice. Comparative analysis between 3xTg-AD-H (ADH/WT) and ADH/TO-DKH mice showed that the expression of genes involved in neuroprotection are significantly altered. Among them, expression of the AD-related genes including Ttr, Enpp2, Kcnj13 and Kl was significantly downregulated in ADH/TO-DKH mice.
2021-03-24 | GSE83996 | GEO
Project description:Purpose: The aim of this study is to evaluate the global gene expression induced by OGG1-BER product 8-oxoG in mouse airways. Methods: RNA extracted from individual mouse lungs (experimental group: n=5) were pooled and a total 1 M-NM-<g RNA was used for Next-Generation Sequencing (NGS) analyses on an Illumina HiSeq 1000 sequencing system. Sequence analysis were performed in duplicate. First- and second-strand synthesis, adapter ligation and amplification of the library were performed using the Illumina TruSeq Sample Preparation Kit as recommended by the manufacturer (Illumina). Library quality was evaluated by using an Agilent DNA-1000 chip on an Agilent 2100 Bioanalyzer. Library DNA templates were quantitated by qPCR using known reference starndards. Cluster formation of the library of DNA templates was performed using the TruSeq PE Cluster Kit v3 (Illumina) and the Illumina cBot workstation. Paired-end, 50-base sequencing was performed with a TruSeq SBS kit v3 (Illumina) on the Illumina HiSeq 1000 by protocols defined by the manufacturer. Base call conversion to sequence reads was performed using CASAVA-1.8.2. Sequence data were analyzed with the Bowtie2, Tophat2 and GFOLD programs. Processed data are presented as reads per kilobase transcript per million (RPKM), normalized to the experimental control (RNA from saline-challenged lungs) and reported as fold change (test/control). Results: We mapped an average of 24.76 million sequence reads per sample and identified 23,337 transcripts in total RNA extracted from lungs of Balb/cJ mice as described in Methods. Approximately 10% of the transcripts showed differential expression between the saline-challenged control and 8-oxoguanine-challeged mouse lungs, with a fold change M-bM-^IM-%3.0. We validated the expression changes of 7 selected pro-inflammatory cytokines and chemokines of interest for our studies by qRT-PCR. Hierarchical clustering followed by Protein ANalysis THrough Evolutionary Relationships database (PANTHER) analysis of differentially expressed genes. Results showed overrepresentation of various biological functions (GO terms) including immune system process (GO:0002376; p=5.24e-12) among others. Pathway analysis (PANTHER) indicated that the most overrepresented pathway was inflammation mediated by chemokine and cytokine (P00031, p=<0.01). In addition to gene expression analysis, we confirmed OGG1M-bM-^@M-"8-oxoG-dependent RAS activation in lungs by active RAS pull-down assays, airways neutrophil accumulation by bronchoalveolar lavage fluid (BALF) differential cell counts and airway inflammation by histological examination (H&E staining) of lung sections. Conclusions: This is the first study at the whole-transcriptome level to show induction of innate immune response gene expression in mouse lungs after exposure to OGG1-BER product 8-oxoG. Balb/cJ mice (5 per group) were intranasally challenged with 8-oxoguanine (1 M-BM-5M, 60 M-BM-5l) for 30, 60 and 120 min. Control group mice were intranasally challenged with saline (60 M-BM-5l). RNA from individual mice whithin the same group was pooled and subjected to deep-sequencing analysis in duplicate using NGS on an Illumina HiSeq 1000 sequencing system. After alignment and processing, the resulting RPKM from treatment groups (8-oxoG-challenged) were normalized to the control group (saline-challenged).
2015-02-02 | E-GEOD-61095 | biostudies-arrayexpress
Project description:Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies.
2024-02-29 | GSE216999 | GEO