Zhang Rui, Deng Patricia, Jacobson Dionna, Li Jin Billy
Department of Genetics, Stanford University, Stanford, California, United States of America.
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China.
PLoS Genet. 2017 Feb 6;13(2):e1006563. doi: 10.1371/journal.pgen.1006563. eCollection 2017 Feb.
Adenosine-to-inosine RNA editing diversifies the transcriptome and promotes functional diversity, particularly in the brain. A plethora of editing sites has been recently identified; however, how they are selected and regulated and which are functionally important are largely unknown. Here we show the cis-regulation and stepwise selection of RNA editing during Drosophila evolution and pinpoint a large number of functional editing sites. We found that the establishment of editing and variation in editing levels across Drosophila species are largely explained and predicted by cis-regulatory elements. Furthermore, editing events that arose early in the species tree tend to be more highly edited in clusters and enriched in slowly-evolved neuronal genes, thus suggesting that the main role of RNA editing is for fine-tuning neurological functions. While nonsynonymous editing events have been long recognized as playing a functional role, in addition to nonsynonymous editing sites, a large fraction of 3'UTR editing sites is evolutionarily constrained, highly edited, and thus likely functional. We find that these 3'UTR editing events can alter mRNA stability and affect miRNA binding and thus highlight the functional roles of noncoding RNA editing. Our work, through evolutionary analyses of RNA editing in Drosophila, uncovers novel insights of RNA editing regulation as well as its functions in both coding and non-coding regions.
腺苷到肌苷的RNA编辑使转录组多样化并促进功能多样性，尤其是在大脑中。最近已经鉴定出大量的编辑位点；然而，它们是如何被选择和调控的，以及哪些具有功能重要性，在很大程度上仍然未知。在这里，我们展示了果蝇进化过程中RNA编辑的顺式调控和逐步选择，并确定了大量功能性编辑位点。我们发现，果蝇物种间编辑的建立和编辑水平的变化在很大程度上可以由顺式调控元件来解释和预测。此外，在物种树中早期出现的编辑事件往往在簇中被更高程度地编辑，并且在缓慢进化的神经元基因中富集，因此表明RNA编辑的主要作用是微调神经功能。虽然非同义编辑事件长期以来被认为发挥着功能作用，但除了非同义编辑位点外，很大一部分3'UTR编辑位点在进化上受到限制，被高度编辑，因此可能具有功能。我们发现这些3'UTR编辑事件可以改变mRNA稳定性并影响miRNA结合，从而突出了非编码RNA编辑的功能作用。我们的工作通过对果蝇RNA编辑的进化分析，揭示了RNA编辑调控及其在编码和非编码区域功能的新见解。
