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A molecular mechanism to regulate neural-specific A-to-I editing during development

ABSTRACT: Using a combination of molecular and genomic approaches we uncover a molecular mechanism that regulates RNA editing in a neural- and development-specific manner. We de novo identified 570 A-to-i editing sites in adult neural RNA-seq data and 6202 sites from re-analyzing L1 neural RNA seq.Comparing editomes during development led to the identification of both neural transcripts that were edited only in one life-stage. The stage-specific editing is largely regulated by differential gene expression during neural development, and proper gene expression of nearly one-third of these differentially expressed genes is dependent on adr-2, the only known A-to-I editing enzyme in C. elegans. However, we also identified a subset of neural transcripts which are edited and expressed throughout development. Interestingly, despite a neural-specific downregulation of adr-2 during development, the majority of sites edited throughout development exhibit increased editing in adult neural cells. Biochemical data suggests that ADR-1, a deaminase deficient member of the Adenosine deaminase acting on RNA (ADAR) family is competing with ADR-2 for binding to specific transcripts early in development. Our data suggest a model where during neural development, ADR-2 levels overcome ADR-1 repression, resulting in increased ADR-2 binding and editing of specific transcripts. Together, our findings reveal tissue- and development-specific regulation of RNA editing and identify a molecular mechanism that regulates ADAR substrate recognition and editing efficiency.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE151916 | GEO | 2020/06/06

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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A molecular mechanism to regulate neural-specific A-to-I editing during development

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