Development of a transcriptomic biomarker to detect histone deacetylase inhibitors (HDACi) in TK6 cells
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PROVIDER: PRJNA690817 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptomic signatures, or biomarkers, of toxicity can facilitate rapid mechanistic analysis of chemicals using high-content transcriptomic data and identification of potential hazards to human health. We developed an 81-gene transcriptomic biomarker, named TGx-HDACi, to detect histone deacetylase inhibitors (HDACi) in TK6 human lymphoblastoid cells after 4 hours of chemical exposure. This work leveraged an established transcriptomic biomarker of DNA damage, TGx-DDI, which was developed by Heng Hong Li et al. (2015); TGx-DDI contains 63 genes and can distinguish between DNA damage-inducing (DDI) and non-DDI agents after 4 hours of exposure in TK6 cells. TGx-HDACi was derived from Templated Oligo-Sequencing (TempO-Seq) whole transcriptome gene expression profiles of 20 reference compounds, consisting of 10 HDACi and 10 non-HDACi compounds. Fourteen of the TGx-HDACi reference compounds are also part of the 28-compound reference set for TGx-DDI. The nearest shrunken centroid (NSC) method was applied to the gene expression profiles and 81 genes were identified that accurately identified HDACi compounds in the NSC probability analysis. The classification performance of TGx-HDACi was validated using an additional set of 11 test compounds (4 HDACi and 7 non-HDACi). Thus far, TGx-HDACi has demonstrated 100% accuracy. The availability of TGx-HDACi increases the diversity of tools that can facilitate mode of action analysis of toxicants using gene expression profiling.
2021-04-14 | GSE164478 | GEO
Project description:Gene expression biomarkers are now available for application in the identification of genotoxic hazards. The TGx-DDI transcriptomic biomarker can accurately distinguish DDI from non-DDI exposures based on changes in the expression of 64 biomarker genes. The bioamarker was originally derived from DNA microarray gene expression profiles of TK6 human lymphoblastoid cells post 4-hour exposure to 28 reference DDI and non-DDI agents [Li et al. 2015]. To broaden the applicability of TGx-DDI, the biomarker was tested using quantitative RT-PCR (qPCR), which is accessible to most molecular biology laboratories. To assess the classification capability of the biomarker using qPCR, a custom 96-well TaqMan qPCR array (TGx-DDI qPCR array) was constructed using the 64 biomarker genes. TK6 cells were exposed to each of the 28 reference agents and their vehicle controls for 4 hours and the expression level of the TGx-DDI genes were profiled using the TaqMan arrays. This study provides reference qPCR expression profiles of the TGx-DDI biomarker for DDI chemical classification using qPCR.
2018-12-21 | GSE121532 | GEO
Project description:Early surgery is vital in the treatment of highly fatal pancreatic cancer (PC). But there is no valuable and non-invasive biomarker to screen PC currently. Studies showed many salivary molecules can detect several systemic diseases. We aimed to investigate whether salivary microRNAs (miRNAs) can act as a biomarker to detect resectable PC.
2013-12-15 | GSE53325 | GEO
Project description:In vitro toxicogenomics signatures to predict mode of action can facilitate chemical screening. We recently demonstrated the use of the TGx-28.65 genomic biomarker (representing: toxicogenomics (TGx), developed using a 28 chemical training set, and comprising 65 genes) in classifying agents as genotoxic (DNA damaging) and non-genotoxic in human lymphoblastoid TK6 cells. Because TK6 cells do not possess cytochrome P450 activity, we confirmed accurate classification in cells co-exposed to 1% 5,6 benzoflavone/phenobarbital-induced rat liver S9 for metabolic activation. However, chemicals may require different types of S9 for activation. Here we conducted experiments in TK6 cells exposed to chemicals in the presence of 2% or 10% Aroclor-induced, or 5% ethanol-induced rat liver S9 to expand TGx-28.65 biomarker application. Gene expression profiles were produced 3-4 hr following a 4 hr co-exposure of TK cells to test chemicals (seven genotoxic and two non-genotoxic, three concentrations, and concurrent solvent controls) and S9. Relative survival and micronucleus frequency was assessed by flow cytometry in cells 20 hr after the exposure. We found that genotoxicity/non-genotoxicity could be accurately predicted for the test compounds using the different S9s. One technical replicate of cells co-treated with dexamethasone and 10% Aroclor-induced S9 was falsely predicted as genotoxic, suggesting caution in using high concentrations of S9. TGx-28.65 correctly classified low concentrations of genotoxic chemicals (those not causing cytotoxicity or micronuclei) as genotoxic, demonstrating that it is a sensitive biomarker of genotoxicity. Overall, the work confirms that different S9s can be used in TK6 cells without impairing predictivity using the TGx-28.65 biomarker.
2016-08-25 | GSE74216 | GEO
Project description:Assessment of the Performance of the TGx-DDI Biomarker to Detect DNA Damage-Inducing Agents Using Quantitative RT- PCR in TK6 Cells
| PRJNA497584 | ENA
Project description:Early surgery is vital in the treatment of highly fatal pancreatic cancer (PC). But there is no valuable and non-invasive biomarker to screen PC currently. Studies showed many salivary molecules can detect several systemic diseases. We aimed to investigate whether salivary microRNAs (miRNAs) can act as a biomarker to detect resectable PC. By Agilent microarray salivary miRNAs were profiled from saliva samples from 8 patients with resectable PC and 8 healthy controls. Candidate biomarkers discovered from the profile were subjected to validation by qPCR.
2013-12-15 | E-GEOD-53325 | biostudies-arrayexpress
Project description:We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible towards treatment with class I histone deacetylase inhibitors (HDACi). However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. Gene expression changes in HDACi entinostat-treated cells identified, the cell cycle protein PLK1 as a potential second target. Indeed, MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1 inhibitors as monotherapy. Moreover, entinostat and PLK1i in combination act synergistically in MYC-driven MB, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect of both drugs as monotherapy and in combination is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with combination. However, further screening of blood-brain barrier penetrating PLK1is is necessary to determine the true potential of the combination. We use microarry to interrogate the expression differences in vehicle, entinostat, volasertib or combination treated cells.
2023-05-15 | GSE220748 | GEO
Project description:The goal of the study was to determine whether low dose HDACi sensitizes human malignant meningioma cells to the cytotoxic capacity of oncolytic herpes simplex virus G47delta. RNA sequencing was used to examine transcriptomic changes mediated by HDACi preexposure before oncolytic virus infection.
2022-08-02 | GSE210178 | GEO
Project description:Histone deacetylase inhibitors are a class of drug which rapidly induce hyperacetylation of histone proteins. Here, we aimed to study the association between HDACi-induced histone acetylation and changes in gene expression. To study the early responses to HDACi treatment we treated cells with three different concentrations of two HDACi, sodium valproate (VPA) and suberoylanilide hydroxamic acid over a short timecourse.
2015-08-31 | GSE65297 | GEO
Project description: Not available
| S-EPMC8138725 | biostudies-literature