Deciphering the functions and regulation of brain-enriched A-to-I RNA editing

Abstract

Adenosine-to-inosine (A-to-I) RNA editing, in which genomically encoded adenosine is changed to inosine in RNA, is catalyzed by adenosine deaminase acting on RNA (ADAR). This fine-tuning mechanism is critical during normal development and diseases, particularly in relation to brain functions. A-to-I RNA editing has also been hypothesized to be a driving force in human brain evolution. A large number of RNA editing sites have recently been identified, mostly as a result of the development of deep sequencing and bioinformatic analyses. Deciphering the functional consequences of RNA editing events is challenging, but emerging genome engineering approaches may expedite new discoveries. To understand how RNA editing is dynamically regulated, it is imperative to construct a spatiotemporal atlas at the species, tissue and cell levels. Future studies will need to identify the cis and trans regulatory factors that drive the selectivity and frequency of RNA editing. We anticipate that recent technological advancements will aid researchers in acquiring a much deeper understanding of the functions and regulation of RNA editing.

Figure 1

Overview. We highlight the major, but not all, discussion topics.

Figure 2

Decreased number of RNA editing sites shared with human sites with increased phylogenetic distance. Phylogenetic relationships between human, chimpanzee, rhesus macaque and mouse are shown on the left. Myr, million years ago. Numbers of A-to-I editing sites that are conserved between human and each of the other three species are shown on the right, with the numbers in non-Alu regions magnified at the bottom. The number of editing sites conserved in human (indicated in the scales) is based on the analysis of the same number of reads from each species. Figure is adapted from ref. .