Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cell line
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA782683 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17012200_1.fastq.gz | Fastqsanger.gz | |||
| SRR17012200_2.fastq.gz | Fastqsanger.gz | |||
| SRR17012201_1.fastq.gz | Fastqsanger.gz | |||
| SRR17012201_2.fastq.gz | Fastqsanger.gz | |||
| SRR17012202_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poor prognosis. Emerging evidence suggests that epigenetic alterations play a crucial role in HCC, suggesting epigenetic inhibition as a promising therapeutic approach. Indeed, the bromodomain and extra-terminal (BET) inhibitors inhibit the proliferation and invasion of various cancers but still lack a strong mechanistic rationale. Here, we identified the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in human HCC cell line HepG2 treated with the BET inhibitors, JQ1, OTX015, or ABBV-075. We analyzed the correlation between DEmRNAs and DElncRNAs in common for the three inhibitors based on their expression profiles and performed functional annotation pathway enrichment analysis. Most of these shared DEmRNAs and DElncRNAs, including some novel transcripts, were downregulated, indicating decreased proliferation/adhesion and increased apoptosis/inflammation. Our study suggests that BET proteins play a crucial role in regulating cancer progression-related genes and provide a valuable resource for novel putative biomarkers and therapeutic targets in HCC.
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Project description:Two human acute lymphoblastic leukemia cell lines were treated with a BET bromodomain inhibitor that blocks BET association with chromatin. These cell lines, MHH-CALL4 and MUTZ-5, each carry translocation of the CRLF2 gene into the IgH locus, and their growth was found to be susceptible to BET inhibition. Gene expression changes were analyzed in each cell line versus vehicle control. Cell were treated for 8 hours with either DMSO or 500nM of the BET bromodomain inhbitor JQ1. Three samples for each treatment were taken and analyzed for each cell line. CEL files were analyzed at both the core and extended gene level by RMA with the Affymetrix Expression Console software.
2012-08-09 | E-GEOD-39995 | biostudies-arrayexpress
Project description:Identification of the mechanisms through which BET inhibitor (OTX-015) stimulates natural killer (NK) activation. RNA-seq was performed comparing vehicle- (DMSO) to OTX-015-treated NK-92 cell line.
2024-01-26 | E-MTAB-12853 | biostudies-arrayexpress
Project description:Two human acute lymphoblastic leukemia cell lines were treated with a BET bromodomain inhibitor that blocks BET association with chromatin. These cell lines, MHH-CALL4 and MUTZ-5, each carry translocation of the CRLF2 gene into the IgH locus, and their growth was found to be susceptible to BET inhibition. Gene expression changes were analyzed in each cell line versus vehicle control.
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Project description:The goal of this experiment was to understand the changes in gene expression in the human basal-like breast cancer cell line HCC1143 following treatment with the MEK inhibitor Trametinib (T), PI3K/mTOR inhibitor BEZ235 (B), the BET inhibition JQ1 (JQ), Trametinib + JQ1 (TJ), or BEZ235 + JQ1(BJ), compared to a DMSO control (D). Samples were treated for 72hr and run in triplicate.
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Project description:The goals of this study are to find drug response genes to different drug combinations in BET inhibitor resistant HepG2 cells. RSEM is taken for consequent data analysis, mapping each sample to the human genome (build hg19) to determine expressions of 57773 transcripts.
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Project description:Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo-and-extra-terminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2). Co-crystal structures revealed binding modes of RVX-208 and its synthetic precursor and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation HepG2 Cells were treated with eitther DMSO or 0.5uM JQ1 or 5uM RVX-208. Three samples per condition, total of nine samples. Inhbitor treatment was carried out for 4h before RNA was extracted. HepG2 cells (ATCC: HB-8065) were maintained in M-NM-1-MEM (Cat.#BE12-169F; BioWhittaker) supplemented with 10 % heat-inactivated foetal calf serum (PAA #A15-152), non-essential amino acids (Cat. #M7145; Sigma), glutamine (Cat.#M11-004; PAA), and vitamins (Cat.#M6895; Sigma). Cells were grown at 37 M-BM-0C in a humidified cabinet at 5 % CO2 (Heraeus Function Line). For experiments, cells were seeded the day prior to treatment at 2x105/ml. Treatments were performed for 4 h so that a final concentration of 0.1 % DMSO (Cat.#D1435; Sigma) was achieved. At harvest, cells were washed once with PBS (Cat.#H15-002; PAA), and lysed in situ using RLT buffer supplemented with 10 M-NM-<l/ml M-NM-2-mercaptoethanol (Cat.#M7522; Sigma). Total RNA was extracted and prepared using RNeasy columns (Cat.#74106 plus; Qiagen) including a Qia shredding step (Cat.#79656; Qiagen) and an on-column DNAse digestion (Cat.#EN0521; Fermentas), according to the manufacturerM-bM-^@M-^Ys instructions. The resulting RNA was quantified and quality controlled using a Nanodrop spectrophotometer (model ND1000; Thermo Fisher). RNA integrity was assessed on a BioAnalyzer (model G2938C; Agilent Laboratories, USA) and all samples had a RNA Integrity Number (RIN) M-bM-^IM-% 9. Labelled sense ssDNA for hybridization was generated from 200 ng starting RNA with the Ambion WT expression kit (Cat.#4411973; Ambion) and the Affymetrix GeneChip WT Terminal Labelling and Controls Kit (Cat.#901525; Affymetrix) according to the manufacturerM-bM-^@M-^Ys instructions. The distribution of fragmented sense ssDNA lengths was measured on the BioAnalyser. The fragmented ssDNA was labelled and hybridized for 17 hours at 45 M-BM-0C on the Affymetrix GeneChip Human Gene 1.0 ST Array (Affymetrix). Chips were processed on an Affymetrix GeneChip Fluidics Station 450 and Scanner 3000 and the affymetrix Command Console (v.3.2.4; Affymetrix) was used to generate CEL files.
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Project description:Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism but is demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, FcγRII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however expression of key target genes such as MYC remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors is in part a consequence of increased Wnt/β-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/β-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies. Total RNA obtained from iBET resistant and sensitive cells
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