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 >1,400 liver-expressed xeno-lncs, many with human and/or mouse orthologs. Xenobiotics representing different MOAs often regulated common xeno-lnc targets: 123 xeno-lncs were dysregulated by > 10 chemicals, and 5 xeno-lncs responded to > 20 of the 27 chemicals investigated; 81 other xeno-lncs served as MOA-selective markers of xenobiotic exposure. Xeno-lnc−protein-coding gene co-expression regulatory network analysis identified xeno-lncs closely associated with exposure-induced perturbations of hepatic fatty acid metabolism, cell division, or immune response pathways, and with apoptosis or cirrhosis. We also identified hub and bottleneck lncRNAs, which are expected to be key regulators of gene expression. This work elucidates extensive networks of xeno-lnc−protein-coding gene interactions and provides a framework for understanding the widespread transcriptome-altering actions of foreign chemicals in a key responsive mammalian tissue.

These files contain supplementary datasets for K Karri and DJ Waxman (2020) Toxicological Sciences, https://doi.org/10.1093/toxsci/kfaa001, PMID:31926019.

Supplemental Figures S1 to S12 are included in a single pdf file.

Individual CSV files are provided for each of the Excel Worksheets.

Full gene and isoform structure information is provided for the set of 5,795 liver-expressed lncRNA genes in the GTF file: Rat_lncRNA_GTF_Karri_Waxman_ToxSci_2020.gtf. Also, see the accompanying GTF_README file.

Gene Networks associated with this dataset are found here:

http://www.ndexbio.org/#/networkset/74ed1c25-2fab-11e9-9f06-0ac135e8bacf?accesskey=838f4dc32739041a462f9ca9a80f628b8194c78d71eaf0ac8d8fef716743c5ab