Srivastava Prashant Kumar, Bagnati Marta, Delahaye-Duriez Andree, Ko Jeong-Hun, Rotival Maxime, Langley Sarah R, Shkura Kirill, Mazzuferi Manuela, Danis Bénédicte, van Eyll Jonathan, Foerch Patrik, Behmoaras Jacques, Kaminski Rafal M, Petretto Enrico, Johnson Michael R
Division of Brain Sciences, Imperial College Faculty of Medicine, London W12 0NN, United Kingdom.
Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, United Kingdom.
Genome Res. 2017 Mar;27(3):440-450. doi: 10.1101/gr.210740.116.
The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine-temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including "neuron projection" and "seizures." Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.
通过RNA编辑对遗传信息进行重新编码有助于蛋白质组的多样性，但人们对疾病中RNA编辑的程度和意义了解甚少。特别是，很少有研究在全基因组水平上调查RNA编辑与疾病之间的关系。在此，我们开发了一个框架，用于全基因组检测在疾病中差异编辑的RNA位点。利用来自癫痫小鼠（毛果芸香碱-颞叶癫痫模型）的100个海马体和100个健康对照海马体的RNA测序数据，我们鉴定出256个RNA位点（与87个基因重叠），这些位点在癫痫病例和对照之间存在显著差异编辑。癫痫小鼠中RNA差异编辑的程度与癫痫发作频率相关，病例组和对照组小鼠之间差异RNA编辑的基因集富含与癫痫高度相关的功能术语，包括“神经元投射”和“癫痫发作”。具有差异RNA编辑的基因优先富集与癫痫有遗传关联的基因。事实上，我们发现它们在患有癫痫性脑病的患者中携带非同义新生突变的基因以及与全身性癫痫相关的常见易感性变异体中显著富集。这些分析揭示了在获得性症状性癫痫中差异RNA编辑的基因与那些导致遗传性癫痫风险的基因之间的功能趋同。综上所述，我们的结果表明RNA编辑在癫痫海马体中对癫痫发作的发生和严重程度可能发挥作用。
