Crosstalk between Receptor and Non-receptor Mediated Chemical Modes of Action in Rat Livers Converges through a Dysregulated Gene Expression Network at Tumor Suppressor Tp53

Abstract

Chemicals, toxicants, and environmental stressors mediate their biologic effect through specific modes of action (MOAs). These encompass key molecular events that lead to changes in the expression of genes within regulatory pathways. Elucidating shared biologic processes and overlapping gene networks will help to better understand the toxicologic effects on biological systems. In this study we used a weighted network analysis of gene expression data from the livers of male Sprague-Dawley rats exposed to chemicals that elicit their effects through receptor-mediated MOAs (aryl hydrocarbon receptor, orphan nuclear hormone receptor, or peroxisome proliferator-activated receptor-α) or non-receptor-mediated MOAs (cytotoxicity or DNA damage). Four gene networks were highly preserved and statistically significant in each of the two MOA classes. Three of the four networks contain genes that enrich for immunity and defense. However, many canonical pathways related to an immune response were activated from exposure to the non-receptor-mediated MOA chemicals and deactivated from exposure to the receptor-mediated MOA chemicals. The top gene network contains a module with 33 genes including tumor suppressor TP53 as the central hub which was slightly up-regulated in gene expression compared to control. Although, there is crosstalk between the two MOA classes of chemicals at the TP53 gene network, more than half of the genes are dysregulated in opposite directions. For example, Thromboxane A Synthase 1 (Tbxas1), a cytochrome P450 protein coding gene regulated by Tp53, is down-regulated by exposure to the receptor-mediated chemicals but up-regulated by the non-receptor-mediated chemicals. The regulation of gene expression by the chemicals within MOA classes was consistent despite varying alanine transaminase and aspartate aminotransferase liver enzyme measurements. These results suggest that overlap in toxicologic pathways by chemicals with different MOAs provides common mechanisms for discordant regulation of gene expression within molecular networks.

A Leveraged Signal-to-Noise Ratio (LSTNR) Method to Extract Differentially Expressed Genes and Multivariate Patterns of Expression From Noisy and Low-Replication RNAseq Data

“…Still, we found that clustering based on 1,510 DEGREEs resulted in interleaved MOA groups, except for PPARA (Figure 4A ). This kind of transcriptional cross-talk among 1,510 DEGREEs has been previously reported for this same dataset, suggesting that downstream pathways elicited by different chemical agents under the same MOA classification can converge to the same regulatory hubs through different molecular cascades and lead to distinctive transcriptional effects; conversely, chemical agents classified under different MOA can exhibit similar transcriptional signatures just as well (Funderburk et al, 2017 ).…”

“…With the LSTNR method, the improvements in homoscedasticity by resolution scaling of Log2FC differences allow experimental designs with multiple groups to be tested by standard ordinary ANOVA techniques. Furthermore, DEGs detected by the LSTNR method capture the same transcriptional signatures at different tiers of statistical stringency with high accuracy; we found the performance of the LSTNR method was so robust that it required less genes than previously reported to discriminate breast cancer phenotypes and hepatotoxic MOAs using the same experimental datasets (Perou et al, 2000 ; Cancer Genome Atlas, 2012 ; Gong et al, 2014 ; Wang et al, 2014 ; Li and Bushel, 2016 ; Funderburk et al, 2017 ). As an added benefit, the LSTNR method can produce noise benchmarking estimates to validate RNAseq experiments against by benchtop techniques, regardless of statistical significance or sample replication levels.…”

miR-1269 promotes cell survival and proliferation by targeting tp53 and caspase-9 in lung cancer

“…It is involved in DNA damage repair, can regulate energy metabolism and also inhibits tumor angiogenesis to suppress the development and progression of cancer. 23 – 26 Moreover, abnormalities in the TP53 signaling pathway were found in the more malignant tumors. It reported that the upregulation of TP53 activated the caspase-9 death pathway.…”

Compound Danshen Dripping Pill Inhibits Retina Cell Apoptosis in Diabetic Rats

“…To reveal the molecular mechanisms underlying in the retinal effects CDDP in diabetic rats, we performed a genome-wide expression profiling analysis on total RNA isolated from the retinas of the HCDDP group and the diabetic group ( n = 3 in each group) ( Hargadon, 2015 ; Funderburk et al, 2017 ; Gambara et al, 2017 ; Li et al, 2017 ). We found that 262 genes were differentially expressed in the retinas of HCDDP-treated rats (fold change >1.5, P < 0.05).…”