Abstract
Heavy metal pollution has been a worldwide prevalent problem, and particularly a threat to ecosystem integrity and animals' health. Previous studies on the mechanisms of heavy metal toxicity have focused on protein-coding genes, whereas most genomic transcripts are long non-coding RNAs (lncRNAs). Although lncRNAs are known to play important regulatory roles in biological processes, their role in heavy metal stress regulation is still not fully understood. We here developed an insect embryo cell model for studying metal toxicity and the underlying regulatory mechanisms. We performed genome-wide screening and functional characterization of lncRNAs induced by two essential and two non-essential heavy metals in Drosophila embryo-derived S2 cells. We identified 4894 lncRNAs, of which 1410 were novel. Forty-one lncRNAs, together with 328 mRNAs, were induced by all the four heavy metals. LncRNA-mRNA co-expression network and pathway enrichment analysis showed that detoxification metabolism, circadian rhythm, and apoptosis regulation pathways were activated in response to heavy metal stress. LncRNA CR44138 was remarkably upregulated in cells exposed to the four heavy metals and was associated with the apoptosis pathway. Expression interference confirmed that CR44138 aggravated cytotoxicity-induced apoptosis in cells under heavy metals stress. This study highlights the important role of lncRNAs in regulating the cellular response to heavy metals. This study also lays the foundation for discovering the novel regulatory mechanisms and developing diagnostic biomarkers of the toxic effects of heavy metal pollutants on organisms.
