Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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High throughput targeted RNA sequencing on HepG2 cell line exposed to multiple concentration levels of drug induced liver injury (DILI) compounds at various different time points_part1

ABSTRACT: This experiment was carried out to investigate the responses of the human liver model (HepG2) cells upon the exposure of various DILI compounds in multiple severity scenarios by varying the concentration. The cells were seeded in 384 well plate format containing 8000 cell per well with 2 days of resting before exposure. The compounds were exposed for 8 and 24 hours. The cells were lysed and the lysate was collected for high throughput targeted RNA-seq with the human whole genome library. The gene expression profiles were analyzed to identify the modulated responses of the cells. This experiment is part of the TransQST project.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Homo sapiens

SUBMITTER: Lukas Wijaya

PROVIDER: E-MTAB-11555 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNFÎ± signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1Î± and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis. We sought to determine the effect of co-exposure of certain drugs associated with idiosyncratic DILI with the cytokine TNFalpha to mimic drug exposure with inflammation signaling in HepG2 cells Human hepatoma HepG2 cells were obtained from American Type Culture Collection (ATCC, Wesel, Germany), cultured in DMEM supplemented with 10% (v/v) FBS, 25 U/mL penicillin and 25 Âµg/mL streptomycin and used for experiments between passage 5 and 20.

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High throughput targeted RNA sequencing on HepG2 cell line exposed to multiple concentration levels of drug induced liver injury (DILI) compounds at various different time points_part1

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