Transcript profiling of putative MTF-1 activating chemicals in wild-type and MTF-1-null MCF-7 cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA640154 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12038200.fastq.gz | Fastqsanger.gz | |||
| SRR12038201.fastq.gz | Fastqsanger.gz | |||
| SRR12038202.fastq.gz | Fastqsanger.gz | |||
| SRR12038203.fastq.gz | Fastqsanger.gz | |||
| SRR12038204.fastq.gz | Fastqsanger.gz |
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Project description:In future high-throughput transcriptomic studies, we propose that the use of cell lines nullizygous for important targets of environmental chemicals will greatly facilitate the interpretation of regulated genes. To provide proof of this concept, we generated transcript profiles from wild-type and MTF-1-null cells exposed to zinc (Zn) and six putative activators of MTF-1 generated using TempO-Seq targeted sequencing of ~3000 human genes. In the absence of chemical exposure, knockout of MTF-1 resulted in expression changes in 44 genes indicating that MTF-1 has some effect on gene expression in the absence of overt activation. Almost all of the genes regulated by Zn and phenoxybenzamine were no longer regulated in the MTF-1-null cells. For the rest of the chemicals, more than half of the genes regulated in the wild-type cells were no longer regulated in the MTF-1-null cells. These studies demonstrate that many of the changes in gene expression after exposure to the putative MTF-1 activators were MTF-1-dependent.
2020-06-17 | GSE152703 | GEO
Project description:In future high-throughput transcriptomic studies, we propose that the use of cell lines nullizygous for important target genes of environmental chemicals will greatly facilitate the interpretation of gene expression profiles. To provide support for this concept, we generated transcript profiles of known or putative NF-kB activators in wild-type and NFKB1-null HeLa cells. Both cell lines were treated with interleukin 1 (IL1beta), tumor necrosis alpha (TNFalpha) or one of two chemicals identified in high throughput assays for NF-kB activity (chlorhexidine diacetate and carbocyanine). The profiles were generated using TempO-Seq targeted sequencing of ~3000 human genes. Almost all of the genes regulated by IL1beta and TNFalpha in wild-type cells were no longer altered in the NFKB1-null cells and approximately half of the genes regulated by Chlorhexidine diacetate and carbocyanine were dependent on NFKB1 for expression changes. These studies demonstrate that many of the changes in gene expression after exposure to the putative NF-kB activators were NFKB1-dependent.
2021-07-01 | GSE153616 | GEO
Project description:Currently, drug resistance of anti-cancer therapy has become the main cause of low survival rate and poor prognosis. Full understanding of drug resistance mechanisms is an urgent request for further development of anti-cancer therapy and improvement of prognosis. Here we present our N-glycoproteomics study of putative N-glycoprotein biomarkers of drug resistance in doxorubicin resistance breast cancer cell line michigan cancer foundation-7 (MCF-7/ADR) relative to parental michigan cancer foundation-7 (MCF-7) cells. Intact N-glycopeptides (IDs) from MCF-7/ADR and MCF-7 cells were enriched with zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC), labeled with stable isotopic diethylation (SIDE), and analyzed with C18-RPLC-MS/MS (HCD with stepped normalized collision energies); these IDs were identifed with database search engine GPSeeker, and the diferentially expressed intact N-glycopeptides (DEGPs) were quantifed with GPSeekerQuan. With target-decoy searches and control of spectrum-level FDR≤1%, 322 intact N-glycopeptides were identifed; these intact N-glycopeptides come from the combination of 249 unique peptide backbones (corresponding to 234 intact N-glycoproteins) and 90 monosaccharide compositions (corresponding to 248 putative N-glycosites). The sequence structures of 165 IDs were confrmed with structure-diagnostic fragment ions. With the criteria of observation at least twice among the three technical replicates,≥1.5-fold change and p value<0.05, 20 DEGPs were quantifed, where fve of them were up-regulated and 15 of them were down-regulated; the corresponding intact N-glycoproteins as putative markers of drug resistance were discussed.
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Project description:Being the most malignant disease among females, breast cancer has morbidity and mortality in the first and second positions among various cancers [1]. Up to now, chemotherapy has been the most common therapy [2]; however, multidrug resistance (MDR) often occurs to give low overall survival rate. Thus, it is urgent to figure out the mechanism of chemotherapy resistance. The first step of drugs to attack tumor cells is to interact with the plasma membrane, and solute carrier (SLC) family proteins are uptake transporters [3]. On the other side, the efflux transporters (such as ATP-binding cassette, ABC) pump drug out of cancer cells [4]. The main mechanism of MDR is the upregulation of ATP-binding cassette (ABC) transporters [5]. Breast cancer resistance protein (ABCG2), multidrug resistance protein (ABCC1) and P-glycoprotein (P-gp) have been extensively studied [6,7]. Formation of CSCs [8], DNA damage [9] and cell apoptosis [10] and epithelial mesenchymal transition (EMT) are other mechanisms of MDR. To zoom in on the correlation between altered glycosylation and drug resistance and to find out the putative biomarkers, MS-based glycoprotomics is a method of choice. Here, we report our N-glycoproteomics study of differential N-glycosylation from the whole cell lysate of MCF-7/ADR CSCs (adriamycin-resistant MCF-7 CSCs) relative to MCF-7 CSCs. Intact N-glycopeptides from both cells were enriched with ZIC-HILIC, isotopically diethylated, mixed with 1:1 ratio, and the mixture was analyzed by C18-RPLC-ESI-MS/MS (HCD with stepped NCE). Differentially expressed N-glycopeptides (DEGPs) were identified and quantified with database search using GPSeeker.
2023-07-04 | PXD036095 | Pride
Project description:Transcriptome analysis of MCF-7 cells exposed for 48 hours to various concentrations of xenoestrogen chemicals. Although biological effects of endocrine disrupting chemicals (EDCs) are often observed at unexpectedly low doses with occasional non-monotonic dose-response characteristics, transcriptome-wide profiles of sensitivities or dose-dependent behaviors of the EDC responsive genes have remained unexplored. Here, we describe expressome analysis for the comprehensive examination of dose-dependent gene responses and its applications to characterize estrogen responsive genes in MCF-7 cells. Transcriptomes of MCF-7 cells exposed to varying concentrations of representative natural and xenobiotic estrogens for 48 hours were determined by microarray and used for computational calculation of interpolated approximations of estimated transcriptomes for 300 doses uniformly distributed in log space for each chemical. The entire collection of these estimated transcriptomes, designated as the expressome, has provided unique opportunities to profile chemical-specific distributions of ligand sensitivities for large numbers of estrogen responsive genes, revealing that at low concentrations estrogens generally tended to suppress rather than to activate transcription. Gene ontology analysis demonstrated distinct functional enrichment between high- and low-sensitivity estrogen responsive genes, supporting the notion that a single EDC chemical can cause qualitatively distinct biological responses at different doses. Expressomal heatmap visualization of dose-dependent induction of Bisphenol A-inducible genes showed a weak gene activation peak at a very low concentration range (ca. 0.1 nM) in addition to the main, strong gene activation peak at and above 100 nM. Thus, expressome analysis is a powerful approach to understanding the EDC dose-dependent dynamic changes in gene expression at the transcriptomal level, providing important information on the overall profiles of ligand sensitivities and non-monotonic responses. Subconfluent density of MCF-7 cells were exposed to various concentrations of xenoestrogen chemicals for 48 hours and then subjected to transcriptomal analysis using Affymetrix U133 version 2 plus microarray.
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Project description:uncultured putative methanotroph Metagenome
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Project description:Since initial regulatory action in 2010 in Canada, bisphenol A (BPA) has been progressively replaced by structurally related alternative chemicals. Unfortunately, many of these chemicals are data-poor, limiting toxicological risk assessment. We used high-throughput transcriptomics to evaluate potential hazards and compare potencies of BPA and 15 BPA alternative chemicals in cultured breast cancer cells. MCF-7 cells were exposed to BPA and 15 alternative chemicals (0.0005 – 100 µM) for 48 hrs. TempO-Seq sequencing (BioSpyder Inc.) was used to examine general toxicological effects and estrogen receptor alpha (ERα)-associated transcriptional changes. Benchmark concentration (BMC) analysis was conducted to identify two global transcriptomic points of departure (tPODs): (a) the lowest pathway median gene BMC and (b) the 25th lowest rank-ordered gene BMC. ERα activation was evaluated using a published transcriptomic biomarker and an ERα-specific tPOD was derived. Genes fitting BMC models were subjected to upstream regulator and canonical pathway analysis in Ingenuity Pathway Analysis. Biomarker analysis identified BPA and eight alternative chemicals as ERα active. Global and ERα tPODs produced highly similar potency rankings with BPAF as the most potent chemical tested, followed by BPA, BPC, 4,4’-BPF, BPAP, BPS, BADGE, 2,4’-BPF, Pergafast201®, D-8, 2,4’-BPS, TGSA, and BPS-MAE. Further, BPA and transcriptionally active alternative chemicals enriched similar gene sets associated with increased cell division and cancer-related processes. These data provide support for future read-across applications of transcriptomic profiling for risk assessment of data-poor chemicals and suggest that several BPA alternative chemicals may cause hazards at similar concentrations to BPA.
2022-08-18 | GSE211183 | GEO
Project description:Transcript profiling of putative NF-kB activators in wild-type and NFKB1-null HeLa cells
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Project description:New approach methodologies (NAMs) aim to accelerate the pace of chemical risk assessment while simultaneously reducing cost and dependency on animal studies. High Throughput Transcriptomics (HTTr) is an emerging NAM in the field of chemical hazard evaluation for establishing in vitro points-of-departure and providing mechanistic insight. In the current study, 1,201 test chemicals were screened for bioactivity at eight concentrations using a 24-hour exposure duration in the human- derived U-2 OS osteosarcoma cell line with HTTr. Assay reproducibility was assessed using three reference chemicals that were screened on every assay plate. The resulting transcriptomics data were analyzed by aggregating signal from genes into signature scores using gene set enrichment analysis, followed by concentration-response modeling of signatures scores. Signature scores were used to predict putative mechanisms of action, and to identify biological pathway altering concentrations (BPACs). BPACs were consistent across replicates for each reference chemical, with replicate BPAC standard deviations as low as 5.6×10-3 µM, demonstrating the internal reproducibility of HTTr-derived potency estimates. BPACs of test chemicals showed modest agreement (R2 = 0.55) with existing phenotype altering concentrations from high throughput phenotypic profiling using Cell Painting of the same chemicals in the same cell line. Altogether, this HTTr based chemical screen contributes to an accumulating pool of publicly available transcriptomic data relevant for chemical hazard evaluation and reinforces the utility of cell based molecular profiling methods in estimating chemical potency and predicting mechanism of action across a diverse set of chemicals.
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