MGMT crosspaths with cGAS/STING pathway to regulate innate immune response in macrophage
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE309787 | GEO | 2026/02/12
REPOSITORIES: GEO
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Project description: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.
2024-01-23 | GSE231419 | GEO
Project description:To identify genes relevant to cold tolerance and the process of overwintering, we sequenced the transcriptomes of wintering and non-wintering adult and larval D. valens using the Illumina HiSeq platform. Differential expression analysis methods for other non-model organisms were used to compare transcript abundances in adults and larvae at two time periods, followed by the identification of functions and metabolic pathways related to genes associated with cold tolerance. We detected 4387 and 6091 differentially expressed genes (DEGs) between sampling dates in larvae and adults, respectively, and 1140 common DEGs, including genes encoding protein phosphatase, very long-chain fatty acids protein, cytochrome P450, and putative leucine-rich repeat-containing proteins. In a GO enrichment analysis, 1,140 genes were assigned to 44 terms, with significant enrichment for cellulase activity, hydrolase activity, and carbohydrate metabolism. KEGG classification and enrichment analyses showed that the lysosomal and purine metabolism pathways involved the most DEGs, the highly enriched terms included autophagy - animal, pentose and glucuronate interconversions and lysosomal processes. We identified 138 candidate genes associated with cold tolerance, including genes with established roles in this trait (e.g., genes encoding trehalose transporter, fructose-1,6-bisphosphatase, and trehalase). Our comparative transcriptome analysis of adult and larval D. valens in different conditions provides basic data for the discovery of key genes and molecular mechanisms underlying cold tolerance.
2021-01-19 | GSE156139 | GEO
Project description:<p>The Gibberellic acid-stimulated Arabidopsis (GASA) gene family encodes a class of cysteine-rich proteins characterized by an N-terminal signal peptide and a conserved C-terminal GASA domain containing 12 cysteine (Cys) residues. These plant-specific small proteins have been identified across various species, where they primarily regulate plant growth and abiotic stress responses. However, the molecular mechanisms by which AtGASA1 and AtGASA4 contribute to Arabidopsis immunity against P.syringae remain unclear. In this study, we found that the gasa1 and gasa4 mutants exhibited increased susceptibility to P. syringae infection compared to Col-0. To elucidate these roles in plant immunity, we performed transcriptomic and metabolomic analyses. Transcriptomic profiling identified 957 differentially expressed genes (DEGs) in the gasa1 and gasa4 mutants upon pathogen infection, with significant enrichment in plant-pathogen interaction, glycerolipid metabolism, and MAPK signaling pathways. Metabolomic analysis revealed 900 differentially accumulated metabolites (DAMs), enriched in pathways including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and biosynthesis of cofactors. Integrated transcriptomic and metabolomic analyses further demonstrated that DEGs and DAMs were co-enriched in key pathways, including plant hormone signal transduction, biosynthesis of various plant secondary metabolites, and cysteine and methionine metabolism. Notably, within the plant hormone signal transduction pathway, we found that AtGASA1 and AtGASA4 regulate the expression of multiple genes involved in the salicylic acid (SA) signaling pathway, such as ICS1, EDS1, PAD4, PR1, and PR5. Consistently, SA levels in the gasa1 and gasa4 mutants were significantly lower than in Col-0. Our findings provide new insights into the immune functions of AtGASA1 and AtGASA4 in plant immunity against P. syringae infection.</p>
2025-07-27 | MTBLS12780 | MetaboLights
Project description:An increasing amount of evidence attest that the tea made by albino tea cultivars processes characteristic aroma and taste, which has been considered as a new potential product in the market. Therefore, flavor formation mechanism of albino tea cultivars have drawn exceeding attention from researchers. In this study, transcriptome, metabolomics, and whole-genome bisulfite sequencing (WGBS) were employed to investigate shading effects on leaf color conversion and biosynthesis of three major secondary metabolites in the Albino tea cultivar ‘Yujinxiang’. The increase of leaf chlorophyll level is the major cause of shaded leaf greening from young pale or yellow leaf. Transcriptome analysis showed differentially expressed genes (DEGs) mainly participated in biosynthesis of amino acids, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, sulfur metabolism, purine metabolism, and pentose and glucuronate interconversions in shading period compared with control group. The result of metabolomics indicated the total catechins level of shading group was significantly decreased than the control; however, the abundance of caffeine was markedly increased, and theanine level was nearly not influenced. Whole-genome DNA methylation analysis revealed that the global genomic DNA methylation patterns of shading period were remarkably altered compared with the control. Furthermore, differentially methylated regions (DMRs) and the DMR-related DEGs between shading and non-shading analysis indicated the DMR-related DEGs were the critical participants in biosynthesis of three major secondary metabolites. To sum up, these findings suggested that the altered levels of DNA methylation may be the main cause for biosynthesis changes of three major secondary metabolites in ‘Yujinxiang’.
2022-12-29 | GSE142753 | GEO
Project description:We compared differentially expressed genes (DEGs) in isolated SCN of female wild-type and GABAergic neuron rev-erb / knockout (KO) mice at ZT12-14. 29 genes are significantly upregulated and 14 genes are statistically downregulated in SCN of KO mice. Aside from the circadian rhythm as an expected top-enriched functional entity, DEGs were enriched with cell surface proteins and associated modulators. Many of these genes are related to neurotransmission or neurological diseases.
2021-03-24 | GSE150840 | GEO
Project description:Negative regulation of the antiviral cytokine IFN-I is critical to prevent host pathology, but is not fully understood. The highly conserved but understudied epigenetic reader and nuclear body protein SP140 represses IFN-I by an unknown mechanism. We describe the mechanism by which SP140 negatively regulates IFN-I, and include RNA-seq of IFNAR KO and SP140 KO IFNAR KO BMMs untreated or treated with 10 ug/mL DMXAA for 4 hours in this dataset. We found that SP140 represses the expression of a novel positive regulator of IFN-I previously annotated as an annexin II receptor, which we rename RESIST (REgulated Stimulator of IFN-I via Stabilization of Transcript). RESIST promotes IFN-I mRNA stability by binding the CCR4-NOT mRNA deadenylase complex and blocking recruitment of the TTP family of RNA-binding proteins, which negatively regulate IFN-I mRNA stability, to CCR4-NOT. Mechanistically, RESIST uses N and C-terminal alpha-helices respectively to either dock to the CCR4-NOT complex or block TTP family binding. Our work reveals a new regulator of IFN-I and a new mechanism regulating IFN-I mRNA stability.
2024-08-28 | GSE269761 | GEO
Project description:Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors. RNA was isolated from parental U87 (U87_EV) and MGMT-transfected U87 (U87_MGMT) triplicate. Pairwise gene expression differences were compared between the two cell lines. Features selected had more than 2-fold up-or down-regulated (P values of >05, unpaired Student’s t-test with Bonferroni multiple testing correction) were identified. Database for annotation, visualization, and integrated discovery23 was used to identify enriched gene ontology (GO) biological themes.24 The GO data mining was conducted at a term specificity level 3.25 The EASE score was set at 0.05 and the minimum number of genes in a category was 5.
2012-09-11 | E-GEOD-40776 | biostudies-arrayexpress
Project description:Background: Epithelial ovarian carcinoma (EOC) is a malignant tumor with high motility in women. Our previous study found that dysregulated NTPCR was associated with the prognosis of ovarian cancer patients, and thus this present study attempted to explore the potential roles of nucleoside-triphosphatase cancer-related (NTPCR) in disease progression. Methods: Expressed level of NTPCR was investigated in ovarian cancer cell lines by RT-qPCR analysis. shRNA targeting NTPCR was generated and transfected into SKOV3 cells to detect the effect of knocking out NTPCR on cell proliferation, cell cycle, cell migration, and invasion. Transcriptomic sequencing and metabolite profiling analysis were performed in shNTPCR groups to identify transcriptome or metabolites alteration that might contribute to ovarian cancer. And finally, we searched the overlapped signaling pathways correlated with differential metabolites and DEGs by integrating analysis. Results: NTPCR was upregulated in EOC cell lines compared with human ovarian epithelium cell IOSE80, especially in SKOV3 and OVCAR-3 (SKOV3 vs IOSE80, P<0.001; OVCAR-3 vs IOSE80, P<0.001). Knocking out NTPCR can induce cell proliferation and S phase arrest, promote migration and invasion in SKOV3 cells. RNA sequencing analysis demonstrated cohorts of differential expressed genes (DEGs) were identified in shNTPCR samples. PPI networks were constructed for DEGs. STAT1 (degree = 43) and OAS2 (degree = 36) were identified as hub genes in network. Several miRNAs together with target genes were predicted to be crucial genes related to disease progression, including hsa-miR-124-3p, hsa-miR-30a-5p, hsa-miR-146a-5, EP300, GATA2, and STAT3. We also screened the differential metabolites from shNTPCR samples, including 22 upregulated and 22 downregulated metabolites. By integrating analysis, eight overlapped pathways were correlated with these DEGs and differential metabolites, such as primary bile acid biosynthesis, protein digestion, and absorption, pentose and glucuronate interconversions. Conclusion: NTPCR might serve as a tumor suppressor in EOC progression. Our results demonstrated that DEGs and differential metabolites were mainly related to several signaling pathways, which might be a crucial role in the progression of ovarian cancer.
2021-12-31 | GSE178486 | GEO
Project description:In this project, TMT labeling quantitative proteomics technology was used to carry out the research, and a total of 4769 proteins were identified. The differentially expressed proteins were screened according to the criteria that the expression multiple changed more than 1.5 times (up-regulated more than 1.5 times or down-regulated less than 0.67 times) and P value < 0.05. The differentially expressed proteins were screened according to the criteria that the expression multiple changed more than 1.5 times (up-regulated more than 1.5 times or down-regulated less than 0.67). Among them, taking 6h VS 36h as an example, 120 differentially expressed proteins were up-regulated and 67 down-regulated. Through GO enrichment and KEGG pathway analysis, it was found that these differentially expressed proteins were mainly involved in important biological processes such as regulation of localization, cellular homeostasis, regulation of ion transmembrane transport, cytoskeleton organization and negative regulation of lymphocyte mediated immunity, and mainly involved in the regulation of important KEGG metabolic pathways such as Legionellosis, Steroid biosynthesis, Pentose and glucuronate interconversions, Adherens junction and Endocytosis.
2024-04-25 | PXD050764 | Pride
Project description:Transcriptomics and functional bioinformatics were used to investigate the potential interactions of undernutrition and the presence of the conceptus at the time of maternal recognition of pregnancy on uterine indicators of metabolism and reproduction. Adult Rasa Aragonesa ewes were allocated to one of two planes of nutrition during 28 days: maintenance energy intake (control; 5 cyclic, 6 pregnant ewes) providing 7.8 MJ of metabolisable energy per ewe and 0.5 maintenance intake (undernourished; 6 cyclic, 7 pregnant ewes) providing 3.9 MJ of metabolisable energy per ewe. RNA from uterine tissue was harvested at slaughter on day 14 of estrus or pregnancy, and hybridized to the Agilent 15K Sheep Microarray chip. Functional bioinformatics analyses were performed using the Dynamic Impact Approach (DIA) and Ingenuity Pathway Analysis. Among metabolic pathways, citrate cycle, oxidative phosphorylation, pentose and glucuronate interconversions and biosynthesis of unsaturated fatty acids were upregulated in control pregnant compared with control cyclic ewes. However, these pathways were not altered in undernourished ewes. The presence of an embryo in undernourished ewes upregulated fatty acid and glycogenic amino acid metabolism. RIG-I and Toll like receptors and chemokine signaling pathways were upregulated by the presence of the embryo in both control and undernourished ewes, but in the latter group the impact was lower. Undernutrition alone upregulated carbohydrate metabolism, but different pathways were altered in cyclic versus pregnant ewes. Citrate cycle, glycolysis/gluconeogenesis, and pentose and glucuronate interconversions were upregulated in undernourished cyclic compared with control cyclic ewes. Glycolysis/gluconeogenesis, pyruvate and propanoate metabolism, beta-alanine and phenylalanine metabolism were upregulated in undernourished pregnant compared with control pregnant ewes, whereas biosynthesis of unsaturated fatty acids and replication and repair were downregulated. Undernutrition alone led to an overall weak activation of immune system pathways both in cyclic and pregnant ewes. However, undernourished cyclic compared with control cyclic ewes had a high activation of NOD-like and RIG-1 like receptor signaling pathways, whereas undernourished pregnant compared with control pregnant ewes only had a weak upregulation of T cell receptor signaling pathways. Overall, data revealed that metabolic and immune adaptations of the uterus to nutrient restriction are dependent on the presence of the conceptus.
2018-03-01 | GSE108176 | GEO