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The C. elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis

ABSTRACT: ADAR proteins alter gene expression both via catalyzing adenosine-to-inosine RNA editing and in an editing-independent manner by binding to target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. To identify important neuronal targets in C. elegans, we performed the first unbiased assessment of the effects of ADR-2, the C. elegans editing enzyme, on the neural transcriptome. We identified the neural editome and gene expression changes associated with the loss of adr-2. As C. elegans lacking adr-2 exhibit reduced chemotaxis, our studies focused on targets that regulate this process. We identified an edited mRNA, clec-41, whose expression is dependent on ADR-2. Expressing clec-41 in adr-2 deficient neural cells restored chemotaxis. This study is the first of its kind in the RNA editing field to span from developing novel methodology for tissue-specific target identification to organismal behavior, significantly advancing our understanding of ADAR functions in neural cells.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE98869 | GEO | 2017/06/13

SECONDARY ACCESSION(S): PRJNA386479

REPOSITORIES: GEO

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Project description:A-to-I RNA editing is widespread in eukaryotic transcriptomes and plays an essential role in the creation of proteomic and phenotypic diversity. Loss of ADARs, the proteins responsible for A-to-I editing, results in lethality in mammals. In C. elegans, knocking out both ADARs, ADR-1 and ADR-2, results in aberrant behavior and abnormal development. Studies have shown that ADR-2 can actively deaminate dsRNA while ADR-1 cannot. However, as most studies of C. elegans ADARs were performed on worms mutated in both ADAR genes, the effects observed cannot be attributed to a single ADAR or to the interactions between ADAR genes. Therefore, we set to study the effects of each C. elegans ADAR on RNA editing, gene expression, protein levels and the contribution of each of ADAR to the phenotypes observed in worms mutated in both genes, in order to elucidate their distinct functions. We found significant differences in the phenotypes observed in worms mutated in a single ADAR gene. Worms harboring adr-1 mutations have a significant reduction in their lifespan, while worms harboring adr-2 mutations have extended lifespan. We also observed severe abnormalities in vulva formation mainly in adr-1 mutants, and we suggest that these phenotypes are a result of an RNA editing independent function of ADR-1. Mutations in each ADAR resulted in expressional changes in hundreds of genes, and a significant downregulation of edited genes. However, very few changes in the protein levels were observed. In addition, we found that ADR-1 binds many edited genes. Our results suggest that ADR-1 has a significant function in the RNA editing process and by altering editing levels it causes the severe phenotypes that we observed. In contrast, a complete lack of RNA editing is less harmful to the worms. Furthermore, our results indicate that the effect of RNA editing on the protein content in the cell is minor and probably the main purpose of these modifications is to antagonize or enhance other gene regulatory mechanisms that act on RNA.

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The C. elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis

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