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Functional investigation of MiR92b-3p for diagnosis and miRNA-based cure in chemically induced liver injury in fish: a project description

Brzuzan P., Woźny M., Florczyk M.

Environmental Biotechnology

2016

Vol. 12, No. 2

40--42

The continued lack of knowledge concerning the molecular background of adverse effects caused by microcystin-LR (MC-LR) is surprising. This toxin requires additional attention, not only for its ability to cause acute poisoning, but also for its ability to initiate cancer in acute doses, and potentially, to promote cancer via chronic exposure to low concentrations in drinking water. Our recent studies on whitefish (Coregonus lavaretus) revealed that long-term exposure to MC-LR resulted in severe liver injury, followed by regeneration of the liver and its unexpected resilience to further toxin uptake. These effects were accompanied by perturbations of hepatic microRNAs (miRNAs) that have target genes involved in cytoskeletal remodeling, cell metabolism, cell cycle regulation, and apoptosis. Among the most pronounced individual alterations, the reduction of MiR92b-3p expression was the most remarkable, and we suggest roles for the miRNA in the aberrant processes of liver cells. This project addresses potential involvement of MiR92b-3p in the as yet unknown regulatory network of MC-induced hepatotoxicity in fish. After a suite of biochemical, physiological, anatomical, and transcriptomic analyses in vitro and in vivo, we will show how MiR92b-3p works in a damaged liver and which processes it targets. Finally, the research will confirm if and how MiR92b-3p can be targeted therapeutically. We expect it to be shown effective enough to pave a way for its use as a tool for treatment of liver damage in fish. What is more, the RNA-based silencing technique that will be used should yield exciting data for our understanding of the system-level biology of vertebrates.

Charakterystyka zjawiska interferencji RNA : podstawy strukturalne i właściwości siRNA

Sierant M., Nawrot B.

Wiadomości Chemiczne

2003

[Z] 57, 7-8

569--585

RNA interference (RNAi) is a natural biological mechanism for sequence-specific posttranscriptional gene silencing triggered by double-stranded RNA (dsRNA) homologous to a silenced gene. RNAi is found in a wide range of eukaryotes including human cells. The natural function of RNAi appears to be protection of a genome against invasion by mobile genetic elements such as transposons and viruses which produce aberrant RNA or dsRNA in a host cell. Specific mRNA degradation prevents transposon and virus replication. The majority of studies on the molecular mechanism underlying RNAi activity has been conducted in vivo using Drosophila melanogaster and Caenorhabditis elegans or in selected mammalian cell cultures. It has been demonstrated that long dsRNA is cleaved to 21–23 nucleotide long fragments by RNase III-like nuclease Dicer. These short interfering RNAs (siRNAs) are essential sequence–specific mediators of RNAi. They are bound by RNAi specific enzymes of nuclease complex RISC that targets mRNA for degradation. In this complex siRNA recognises, binds and cleaves the target mRNA. Cleavage occurs in the middle of the mRNA region recognized by the siRNA. The second model, which has been proposed for RNAi to explain the mechanism by which siRNA direct target mRNA destruction, requires RNA-dependent RNA polymerase (RdRP) to convert the target mRNA into dsRNA. RdRP is hypothesized to use antisense strand of siRNA as a primer in mRNA templated synthesis of complementary chain RNA. The resulting dsRNA is proposed to be cleaved then by Dicer for generation of secondary siRNA. Short interfering RNAs can be synthesized chemicaly or by in vitro transcription with T7 RNA polymerase, or expressed from siRNA coding vectors in the cells. These 21-nt siRNA duplexes cause efficent inhibition of exogenous and endogenous genes expression in a sequence-specific manner. Detailed analysis of potential modifications, that can be introduced into siRNA strands shows, that chemical modifications of sense strand are tolerated without loss of RNAi activity. However, some modification of antisense strand of siRNA (especially in the middle of the chain as well as modification of the 5’end) completely abolish RNAi. These results indicate that two strands of siRNA have different function in RNAi. RNAi approach can be broadly used for analysis of gene functions, and, what is even more important, this phenomenon can be used for searching new agents for therapeutic applications.