Contextualization of causal regulatory networks from toxicogenomics data applied to drug-induced liver injury

Toxicol Lett. 2021 Jul 3;350:40-51. doi: 10.1016/j.toxlet.2021.06.020. Online ahead of print.

Abstract

In recent years, network-based methods have become an attractive analytical approach for toxicogenomics studies. They can capture not only the global changes of regulatory gene networks but also the relationships between their components. Among them, a causal reasoning approach depicts the mechanisms of regulation that connect upstream regulators in signaling networks to their downstream gene targets. In this work, we applied CARNIVAL, a causal network contextualisation tool, to infer upstream signaling networks deregulated in drug-induced liver injury (DILI) from gene expression microarray data from the TG-GATEs database. We focussed on six compounds that induce observable histopathologies linked to DILI from repeated dosing experiments in rats. We compared responses in vitro and in vivo to identify potential cross-platform concordances in rats as well as network preservations between rat and human. Our results showed similarities of enriched pathways and network motifs between compounds. These pathways and motifs induced the same pathology in rats but not in humans. In particular, the causal interactions "LCK activates SOCS3, which in turn inhibits TFDP1" was commonly identified as a regulatory path among the fibrosis-inducing compounds. This potential pathology-inducing regulation illustrates the value of our approach to generate hypotheses that can be further validated experimentally.

Keywords: Causal reasoning; Drug-induced liver injury (DILI); Network contextualization; Pathway footprints; Signaling networks; Toxicogenomics.