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...外源性物质暴露可异常调控哺乳动物肝脏内的数百个蛋白编码基因，进而影响诸多生理过程并诱发多样的毒理学反应。目前针对外源性物质对长链非编码RNA（long noncoding RNAs, lncRNAs）的影响研究仍较为匮乏，而此类RNA中有不少具备重要的调控功能。本研究构建了一套计算框架，用于筛选兼具强功能活性与基因调控潜力的肝脏表达型、外源性物质应答性长链非编码RNA（xeno-lncs），并阐明外源性物质暴露对其基因调控网络的影响。本研究利用经27种代表性作用机制（mechanisms of action, MOAs）单一化学品处理的雄性大鼠RNA测序（RNA-seq）数据集，组装了外源性物质暴露大鼠肝脏的长链非编码转录组。本研究将同源基因分析与共表达数据、因果推断方法相结合，以推断长链非编码RNA的功能，并推导基因调控网络——包括长链非编码RNA对蛋白编码基因表达及生物通路的因果调控效应。本研究发现……