Widespread dysregulation of long non-coding genes associated with fatty acid metabolism, cell division, and immune response gene networks in xenobiotic-exposed rat liver

Xenobiotic exposure dysregulates hundreds of protein-coding genes in mammalian liver, impacting many physiological processes and inducing diverse toxicological responses. Little is known about xenobiotic effects on long noncoding RNAs (lncRNAs), many of which have important regulatory functions. Here, we present a computational framework to discover liver-expressed, xenobiotic-responsive lncRNAs (xeno-lncs) with strong functional, gene regulatory potential and elucidate the impact of xenobiotic exposure on their gene regulatory networks. We assembled the long non-coding transcriptome of xenobiotic-exposed rat liver using RNA-seq datasets from male rats treated with 27 individual chemicals, representing seven mechanisms of action (MOAs). Ortholog analysis was combined with co-expression data and causal inference methods to infer lncRNA function and deduce gene regulatory networks, including causal effects of lncRNAs on protein-coding gene expression and biological pathways. We discovered...