AUTHOR=Souza Terezinha , Trairatphisan Panuwat , Piñero Janet , Furlong Laura I. , Saez-Rodriguez Julio , Kleinjans Jos , Jennen Danyel 

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

JOURNAL=Frontiers in Genetics

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00527

DOI=10.3389/fgene.2018.00527

ISSN=1664-8021

ABSTRACT=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. 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 AR, E2F1, E2F4, ETS1, GATA2, TFAP2C and YY1 as the important regulatory transcription factors of dark genes for all most-DILI compounds with evidences across multiple functional mapping approaches while JUND and MYC are found to be associated with dark genes that 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 in toxicological studies.