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In toxicogenomics, functional annotation is an important step to gain additional insights into genes with aberrant expression that drive pathophysiological mechanisms. Nevertheless, there exists a gap on annotation of these genes which often hampers the interpretation of results and limits their applicability in translational medicine. In this study, we evaluated the coverage of functional annotations of differentially expressed genes (DEGs) induced by 10 selected compounds from the TG-GATEs database identified as high- or no-risk in causing drug-induced liver injury (most-DILI or no-DILI, respectively) using  in vitro  human data. Functional roles of DEGs not present in the most common biological annotation databases – termed “dark genes” – were unveiled via literature mining and via the identification of shared regulatory transcription factors or signaling pathways. Our results demonstrated that there were approximately 13% of dark genes induced by these compounds  in vitro  and we were able to obtain additional relevant information for up to 76% of those. Using interactome data from several sources, we have uncovered genes such as  LRBA , and  WDR26  as highly connected in the protein network that play roles in drug response. Genes such as  MALAT1, H19 , and  MIR29C  – whose links to hepatotoxicity have been confirmed – were identified as markers for the most-DILI group and appeared as top hits across all literature-based mining methods. Furthermore, we investigated the potential impact of dark genes on liver toxicity by identifying their rat orthologs in combination with their correlation to drug-induced liver pathologies observed  in vivo  following chemical exposure. We identified a set of important regulatory transcription factors of dark genes for all most-DILI compounds including E2F1 and JUND with supporting evidences in literature and we found  Magee1  correlated with chemically induced bile duct hyperplasia and adverse responses at 29 days in rats  in vivo . In conclusion, in this study we show the potential role of these poorly annotated genes in mechanisms underlying hepatotoxicity and offer a number of computational approaches that may help to minimize current gaps in gene annotation and highlight their values as potential biomarkers in toxicological studies.

Embracing the Dark Side: Computational Approaches to Unveil the Functionality of Genes Lacking Biological Annotation in Drug-Induced Liver Injury