Differential Expression of Long Noncoding RNAs in the Livers of Female B6C3F1 Mice Exposed to the Carcinogen Furan

Abstract

The mammalian genome is transcribed into mRNAs that code for protein and a broad spectrum of other noncoding (nc) RNA products. Long ncRNAs (lncRNA), defined as ncRNA species > 200 nucleotides long, are emerging as important epigenetic regulators of gene expression that are involved in a spectrum of biological processes of relevance to toxicology. We conducted a gene expression profiling study in the livers of female B6C3F1 mice exposed to the carcinogen furan at 0.0, 1.0, and 2.0mg/kg (noncarcinogenic doses) and at 4.0 and 8.0mg/kg (carcinogenic doses) for 3 weeks. LncRNA differential expression showed a nonlinear dose response with none differentially expressed at 1.0 or 2.0mg/kg, 2 lncRNAs at 4.0mg/kg furan, and 83 at 8mg/kg, representing 13.3% (83/632) of the total number of differentially expressed transcripts. Among the lncRNAs observed, two lncRNAs examined showed transcriptional clustering with nearby protein-coding genes. LincRNA-p21 is an antisense transcript that is 15kb downstream from Cdkn1a locus and appears to be cotranscribed with the protein coding gene Cdkn1a at 8.0mg/kg furan. In a separate independent study, RNA samples from the livers of mice administered benzo(a)pyrene also demonstrated increased levels of Cdkn1a and the antisense lincRNA-p21 transcript. These data demonstrate that lncRNAs are transcriptional targets of furan exposures associated with levels of furan that are cytotoxic and induce cell proliferation. In addition, certain lncRNA transcripts are associated with the expression of nearby coding protein genes. We hypothesize that lncRNAs have potential as epigenetic biomarkers of carcinogenic exposures.