Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

O6-Methylguanine DNA Methyltransferase Regulates Beta-glucan Trained Immunity of Macrophages

ABSTRACT: Trained immunity is the heightened state of innate immune memory that enhances immune response resulting in nonspecific protection. Epigenetic changes and metabolic reprogramming are critical steps that regulate trained immunity. In this study, we reported the involvement of O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme of lesion induced by alkylating agents, in regulation the trained immunity induced by β-glucan (BG). Pharmacological inhibition or silencing of MGMT expression altered LPS stimulated pro-inflammatory cytokine productions in BG-trained bone marrow derived macrophages (BMMs). Targeted deletion of Mgmt in BMMs resulted in reduction of the trained responses both in vitro and in vivo models. The transcriptomic analysis revealed that the dampening trained immunity in MGMT KO BMMs is partially mediated by ATM/FXR/AMPK axis affecting the MAPK/mTOR/HIF1α pathways and the reduction in glycolysis function. Taken together, a failure to resolve a DNA damage may have consequences for innate immune memory.

ORGANISM(S): Mus musculus

PROVIDER: GSE231419 | GEO | 2024/01/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Histone modification and RNA changes in macrophages exposed to Beta-glucan and Fumarate

Project description:Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as Beta glucan. We apply an epigenomic approach to characterize the molecular events involved in fumarate or BG induced trained innate immunity. ChIP-seq and RNA-seq data were generated. This analysis identified epigenetic programs in trained macrophages, with fumarate exposure inducing a small subset of BG-induced histone acetylation and methylation changes.

2016-11-01 | GSE86940 | GEO

Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to apoptosis due to mismatch-repair overload. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair mechanisms, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT transfection. O6-MeG signatures were highly similar to mutational signatures of patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes, suggesting an additional transcription-associated contribution to its repair. These data provide high resolution insight on how O6-MeG formation and repair is impacted by genome structure and regulation. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

2023-12-12 | GSE249155 | GEO

Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to cell cycle arrest and apoptosis. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT. O6-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes in TMZ-exposed cells and naked DNA proposing an indirect influence of transcription to O6-MeG formation. These data provide high resolution insight on how O6-MeG formation and repair is impacted by genome structure and nucleotide sequence. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

2024-10-30 | GSE279423 | GEO

Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

Project description:Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity.

2017-12-15 | GSE108098 | GEO

O6-Methylguanine DNA Methyltransferase Regulates Beta-glucan Trained Immunity of Macrophages

Project description:O6-Methylguanine DNA Methyltransferase Regulates Beta-glucan Trained Immunity of Macrophages

| PRJNA965794 | ENA

Cycad Genotoxin Methylazoxymethanol (MAM) Modulates Cellular Pathways Involved in Cancer and Neurodegenerative Disease

Project description:Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of young adult mice treated with a single systemic dose of MAM display DNA damage (O6-methylguanine lesions) that peaks at 48 hours and decline to near-normal levels at 7 days post-treatment. By contrast, at this time, MAM-treated mice lacking the gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), showed persistent O6-methylguanine DNA damage. The DNA damage was linked to cell-signaling pathways that are perturbed in cancer and neurodegenerative disease. These data are consistent with the established carcinogenic and developmental neurotoxic properties of MAM in rodents, and they support the proposal that cancer and neurodegeneration share common signal transduction pathways. They also strengthen the hypothesis that early life exposure to the MAM glucoside cycasin has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for medicine and/or food. Exposure to environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer’s disease, as well as cancer. Mouse brains from eleven-week-old male C57BL6 wild-type and Mgmt-/- mice were exposed to either MAM or Vehicle for 6 hr, 24 hr, 48 hr, 168 hr. Five or six mice per group for a total of 94 mice.

2013-01-10 | E-GEOD-26600 | biostudies-arrayexpress

Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression

Project description:Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic based therapies. Here we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the SN1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data show that RAD18 is part of the O6-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevents glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolishes the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes the mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.

2022-04-01 | PXD028683 | Pride

Transcriptional remodeling of primary human monocytes exposed to itaconate and its derivatives in the context of trained immunity

Project description:Trained immunity is a phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to certain microbial components, altering their responses to future exposures. This study profiled the transcriptome of human monocytes and in vitro differentiated macrophages, exposed to a combination of LPS, BG, DMI, or Itaconate.

2023-06-26 | GSE212282 | GEO

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

2018-07-13 | GSE113816 | GEO

Cycad Genotoxin Methylazoxymethanol (MAM) Modulates Cellular Pathways Involved in Cancer and Neurodegenerative Disease

2013-01-10 | GSE26600 | GEO