Whole-body and liver-specific ATF4–knockout mice are used to evaluate the role of ATF4 transcription factor in the unfolded protein response (UPR). ATF4 directs a small subset of UPR gene expression, and deletion of ATF4 in the liver triggers enhanced oxidative stress, disrupts cholesterol metabolism, and enhances cell death.
Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.
This study measured changes in global mRNA translation in response to ER stress. The analysis suggests that translation of a majority of gene transcripts is either repressed or resistant, whereas select key regulators are subject to preferential translation. From this last group, IBTKα is identified as a novel target of the UPR central to cell fate.
Background: eIF2␣-P induced GADD34 and constitutively expressed CReP target PP1c to dephosphorylate eIF2␣-P to dictate translation control of the ISR. Results: Differential expression of GADD34 and CReP is regulated by upstream ORF (uORF)-mediated ribosome reinitiation. Conclusion: uORFs regulate differential expression of GADD34 and CReP and are important for cell adaptation to stress. Significance: Regulation of eIF2␣-P is central for protein homeostasis and cell viability.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.