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De Novo Profiling of Long Non-Coding RNAs Involved in MC-LR-Induced Liver Injury in Whitefish: Discovery and Perspectives

ABSTRACT: Microcystin-LR (MC-LR) is a potent hepatotoxin for which a substantial gap in knowledge persists regarding the underlying molecular mechanisms of liver toxicity and injury. Although long non-coding RNAs (lncRNAs) have been extensively studied in model organisms, our knowledge concerning the role of lncRNAs in liver injury is limited. Given that lncRNAs show low levels of sequence conservation, their role becomes even more unclear in non-model organisms without an annotated genome, like whitefish (Coregonus lavaretus). The objective of this study was to discover and profile aberrantly expressed polyadenylated lncRNAs that are involved in MC-LR-induced liver injury in whitefish. Using RNA sequencing (RNA-Seq) data, we de novo assembled a high-quality whitefish liver transcriptome. This enabled us to find 94 differentially expressed (DE) putative evolutionary conserved lncRNAs, such as MALAT1, HOTTIP, HOTAIR or HULC, and 4429 DE putative novel whitefish lncRNAs, which differed from annotated protein-coding transcripts (PCTs) in terms of minimum free energy, guanine-cytosine (GC) base-pair content and length. Additionally, we identified DE non-coding transcripts that might be 3′ autonomous untranslated regions (3′UTRs) of mRNAs. We found both evolutionary conserved lncRNAs as well as novel whitefish lncRNAs that could serve as biomarkers of liver injury.

ORGANISM(S): Coregonus lavaretus

PROVIDER: GSE168454 | GEO | 2021/03/08

REPOSITORIES: GEO

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Project description:Microcystins (MCs) are cyclic hepatotoxins produced worldwide by various species of cyanobacteria. Their structure includes two variable amino acids (AAs) and most of the studies focused on the most toxic variant: the microcystin LR (MC-LR). However, more than 80 MC variants have been described to date. Despite ingestion being the major pathway of human exposure, few in vivo studies have demonstrated macroscopic effects on the gastro-intestinal tract, but no data are available on the affected pathways by several variants on intestinal cells. Here, using a non-selective method, we investigated for the first time the effect of MC-RR and MC-LR on the human intestinal cell line Caco-2 and compared their response at the pangenomic scale. The cells were incubated for 4 hrs or 24 hrs with the same range of sub-lethal concentrations of MC-RR or MC-LR. Low effects were observed for both variants after a short-term exposure. On the contrary, dose-dependent modulations of the genes transcription levels were noticed with MC-RR and MC-LR after 24 hrs. Furthermore, the genomic profiles induced by both variants were similar suggesting a common toxicity mechanism but with higher modulation following MC-LR than MC-RR exposure. However, the functional annotation revealed major differences between the variants effects. Indeed, the well-known MC-LR affected mainly two pathways, the oxidative stress response and the cell cycle regulation, which did not elicit significant alteration following MC-RR exposure. This work is the first comparative description of the MC-LR and MC-RR effects on a human intestinal cell model. It allowed us to suggest differences in the mechanism of toxicity for MC-RR and MC-LR. These results illustrate that the toxicity of MC variants remains a key point for risk assessment. Differentiated Caco-2 cells were exposed to microcystins in free FCS culture medium for either 4 or 24 hours. Sub-lethal concentrations of 10, 50 and 100 M-BM-5M of MC-LR or MC-RR were chosen for 4 hours, while 1, 5 and 10 M-BM-5M were selected for 24 hours. For each condition (including the controls), the solvent concentration was fixed to 2% EtOH for MC-LR and 1.5% of 80% MeOH for MC-RR. Four to five culture replicates per condition were done.

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De Novo Profiling of Long Non-Coding RNAs Involved in MC-LR-Induced Liver Injury in Whitefish: Discovery and Perspectives

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