Mapping Spatio‐temporal ADAR Editing Landscapes in Neurodevelopment

Abstract

BackgroundTranscriptome diversity, more specifically RNA editing, plays a fundamental role in neurodevelopment and plasticity. One form of RNA editing, catalyzed by Adenosine Deaminases Acting on RNA (ADAR), creates variant isoforms, many of which are involved in important pathways including differentiation, proliferation, cell‐migration, vesicular trafficking, and receptor endocytosis and recycling. Immune activation can lead to changes in gene expression of one specific isoform, ADAR1p150, altering RNA editing landscapes causing changes to the structure and/or function of proteins, which, in turn, may contribute to the broad spectrum of symptoms seen in many neurological disorders.MethodsUsing publically available RNA‐seq datasets combined with our computational pipeline, Automated Isoform Diversity Detective (AIDD), including our novel statistical approach using Guttman scaling, we examine global ADAR‐editing patterns in different regions and time points during brain development. In addition, to explore the more subtle nuances of editing changes, nucleotide frequencies at individual genes within the excitome are used to determine differential expression of variant isoform.ResultsADAR expression and global ADAR editing patterns are significantly different between both brain regions and gestational week. Additionally, ADAR editing landscapes are spatially and temporally regulated, especially prominent in the excitome, a collection of 109 experimentally confirmed ADAR editing sites. A few editing sites are unique to each developing region, while other sites are differentially edited across gestational weeks. Finally, serotonin receptor 2C (5HTR2C), with 5 well‐studied editing sites, is differentially edited early in development in choroid plexus and later in development in the basal ganglia, but not edited in the cerebellum.ConclusionsMapping the global RNA editing patterns during neurodevelopment offers insights into mechanisms behind the evolution of higher cognitive function, as well as into molecular pathways underpinning neurological disease. Changes in the excitome variant isoform expression can potentially be used as diagnostic, prognostic and/or therapeutic biomarkers in neurodevelopmental, psychiatric, and degenerative disorders.