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Summary: 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.

Symbol: Gene expression in chow or HFD-fed OGG1-/- livers

HDAC1 modulates OGG1-initiated oxidative DNA damage repair, brain aging, and Alzheimer's disease pathology

(Mus musculus)

HTP Dataset Index

High-Throughput (HTP) Dataset Index metadata provided by MGI

ID: ArrayExpress:GSE115437

Tags: WT vs. mutant, anatomical structure, genotype

Summary: 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. ChIP-Seq and RNA-Seq of mouse hippocampus, and RNA-Seq of GFAP+ nuclei were isolated from mouse cortex

Symbol: HDAC1 modulates OGG1-initiated oxidative DNA damage repair, brain aging, and Alzheimer's disease pathology

Genome-wide analysis of 6 month old hippocampal gene expression in Ogg1- and/or Mutyh-deficent mice

(Mus musculus)

HTP Dataset Index

High-Throughput (HTP) Dataset Index metadata provided by MGI

ID: ArrayExpress:GSE73029

Tags: WT vs. mutant, genotype

Summary: Oxidative DNA damage has been associated with cognitive decline. The Ogg1 and Mutyh DNA glycosylases cooperate to prevent mutations caused by 8-oxoG, a major premutagenic oxidative DNA base lesion. Here, we have examined behavior and cognitive function in mice deficient of these glycosylases. We found that Ogg1-/-Mutyh-/- mice were more active and less anxious and that their learning ability was impaired. In contrast, Mutyh-/- mice showed moderately improved memory compared to WT. There was no change in genomic 8-oxoG levels, suggesting that Ogg1 and Mutyh play minor roles in global repair in adult brain. Notably, transcriptome analysis of hippocampus revealed that differentially expressed genes in the mutant mice belong to pathways known to be involved in anxiety and cognitive function. Thus, beyond their involvement in DNA repair, Ogg1 and Mutyh modulate cognitive function and behavior, and related hippocampal gene expression, suggesting a novel role for 8-oxoG in regulating adaptive behavior. The mRNA profiles from hippocampus of WT, Ogg1-/-, Mutyh-/- and Ogg1-/- Mutyh-/- C57BL/6 mice at 6month of age were generated by RNA sequencing using Illumina Hiseq 2000

Symbol: Genome-wide analysis of 6 month old hippocampal gene expression in Ogg1- and/or Mutyh-deficent mice

RNA-seq of mouse heart that is both heart SOD2 knockout and deficient for mitochondrial DNA repair

(Mus musculus)

HTP Dataset Index

High-Throughput (HTP) Dataset Index metadata provided by MGI

ID: ArrayExpress:E-MTAB-6534

Tags: WT vs. mutant, genotype

Summary: 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.

Sirtuin 3 is a common target of non-steroidal anti-inflammatory drugs to induce gastric cancer cell death and gastric mucosal injury.

(Rattus norvegicus)

HTP Dataset Index

High-Throughput (HTP) Dataset Index metadata provided by RGD

ID: GEO:GSE201565

Tags: unclassified

Summary: Nonsteroidal anti-inflammatory drugs (NSAIDs), the quintessential medicines to treat pain and inflammatory conditions, induce cell death in human cancer cells, as repurposed anticancer agents, and in normal gastric mucosa, as a major side effect. The subcellular target/s of NSAIDs that leads to the cell death remained elusive so far. Here, by venturing transcriptomics followed by functional validation, we, for the first time, identified mitochondrial deacetylase Sirtuin 3 (Sirt3) as a non-canonical target of NSAIDs whose depletion induced the hyperacetylation of mitochondrial proteome, OGG1 depletion, mtDNA damage, electron transport chain defect associated mitochondrial dysfunction and finally cell death. Silencing of Sirt3 in AGS cells (a human gastric adenocarcinoma cell line) significantly aggravated NSAID-induced cytopathology. Whereas, honokiol mediated induction of Sirt3 corrected the NSAID-induced transcriptome alteration and gastropathy in rodent model. Together, the results identify Sirt3 as a common target used by NSAIDs to induce gastric carcinoma cell death and gastric mucosal injury.

Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum

(Mus musculus)

HTP Dataset Index

High-Throughput (HTP) Dataset Index metadata provided by MGI

ID: ArrayExpress:E-GEOD-62594, GEO:GSE62594

Tags: strain study, sex, baseline

Summary: The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of genetic alterations in OGG1 in pathogenesis of autism. Gene expression profiles in the cerebellum of 8 weeks old BTBR T+tf/J mice that exhibit an autism-like behavioral phenotype and control C57BL/6J mice were examined using high-throughput Agilent whole genome 8x60K mouse microarrays.

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