Long Non-Coding RNAs: A Novel Paradigm for Toxicology

Abstract

Long non-coding RNAs (lncRNAs) are over 200 nucleotides in length and are transcribed from the mammalian genome in a tissue-specific and developmentally regulated pattern. There is growing recognition that lncRNAs are novel biomarkers and/or key regulators of toxicological responses in humans and animal models. Lacking protein-coding capacity, the numerous types of lncRNAs possess a myriad of transcriptional regulatory functions that include cis and trans gene expression, transcription factor activity, chromatin remodeling, imprinting, and enhancer up-regulation. LncRNAs also influence mRNA processing, post-transcriptional regulation, and protein trafficking. Dysregulation of lncRNAs has been implicated in various human health outcomes such as various cancers, Alzheimer's disease, cardiovascular disease, autoimmune diseases, as well as intermediary metabolism such as glucose, lipid, and bile acid homeostasis. Interestingly, emerging evidence in the literature over the past five years has shown that lncRNA regulation is impacted by exposures to various chemicals such as polycyclic aromatic hydrocarbons, benzene, cadmium, chlorpyrifos-methyl, bisphenol A, phthalates, phenols, and bile acids. Recent technological advancements, including next-generation sequencing technologies and novel computational algorithms, have enabled the profiling and functional characterizations of lncRNAs on a genomic scale. In this review, we summarize the biogenesis and general biological functions of lncRNAs, highlight the important roles of lncRNAs in human diseases and especially during the toxicological responses to various xenobiotics, evaluate current methods for identifying aberrant lncRNA expression and molecular target interactions, and discuss the potential to implement these tools to address fundamental questions in toxicology.

Keywords: gene regulation; long non-coding RNAs.; toxicoepigenomics.

FIG. 1

LncRNA transcriptional start sites and examples of lncRNA functions. (A) LncRNAs are transcribed from the Watson or Crick strand and the arrows represent lncRNA transcriptional start sites that are intergenic, exonic, in enhancer regions, or in regions distal to protein-coding genes. (B) LncRNAs, such as HOTAIR and HOTTIP, modify nuclear architecture through organization of histone modification proteins (top), whereas other lncRNAs (bottom) influence transcription by localizing transcription factors or inhibiting RNA polymerase II. (C) LncRNAs regulate alternative splicing of nascent protein-coding transcripts by intron retention. (D) LncRNAs modulate translation through miRNA sequestration (left), interacting with mRNA to increase transcript stability or inhibit translation (middle), and mRNA turnover (right). (E) LncRNAs are also emerging as possible extracellular signals in exosomal shuttle RNA to regulate the biological functions of neighboring or distal cells.