Integrative genomic analysis of adenosine-to-inosine editing in Alzheimer's disease

项目总结 通过腺苷到肌苷(A-to-I)RNA编辑进行的转录后修饰是导致 人类大脑中RNA序列的全球多样性。A-to-I编辑发生在单独的腺苷 (“选择性编辑”)或同一转录本上延伸区域的多个相邻腺苷(“超- 正在编辑‘)。这些碱基特异的改变发生在大多数神经元和非神经元表达的基因上，并且 是正常大脑功能所必需的。A-to-I编辑已被证明可以影响替代剪接、重新编码 蛋白质的氨基酸序列，改变miRNAs与其靶点结合的能力，并改变其稳定性 RNA二级结构。此外，最近的研究表明，这些修饰在 大脑，编辑水平的变化与神经发育和神经退行性疾病的病因有关， 包括阿尔茨海默病(AD)。然而，在对神经病理作用的理解上仍存在重大差距。 在AD大脑中进行A-to-I编辑。绝大多数站点可能会在不同的 阿尔茨海默病的细胞类型、脑区和不同程度的痴呆症。然而，在这样的背景下，现状是- 对RNA编辑的依赖调节可以概括为很少或没有。此外，虽然大多数努力都有 独立研究了个别精选的A-to-I编辑网站，对其作用的研究完全缺乏 AD中A-to-I超编辑和超编辑基因的研究，它们对转录和 翻译法规。最后，虽然现有的关于RNA编辑调控的研究主要集中在 腺苷脱氨酶作用于RNA酶，顺式作用的遗传调控作用(编辑数量性状 基因座[edQTL])一直研究不足，动力不足。这项建议将利用大型- 规模基因组学和联合会的努力，以阐明正常的功能和高度调控的RNA编辑位点 老龄化和AD的规模达到了以前不可能达到的水平。目前的提议旨在克服现有的知识 差距：目标1)解决基础神经科学研究的未得到满足的需求，以获取基础知识 正常衰老和阿尔茨海默病多个脑区和细胞类型的RNA编辑调节；目的2)整合 来自大型队列的个体遗传信息，以构建强大的edQTL图谱并发现可信的AD组 通过改变大脑中的RNA编辑水平来发挥致病作用的风险基因座；目标3)应用数据- 驱动的计算方法来注释重要的功能RNA编辑站点并确定其优先顺序 编辑与AD密切相关的基因，从而促进我们对AD复杂病因的理解 RNA修饰的透镜。这一提议的结果将产生更完整的分子图景 和阿尔茨海默病的遗传格局，将推进新的治疗靶点的识别。

PROJECT SUMMARY Post-transcriptional modifications by adenosine-to-inosine (A-to-I) RNA editing are a major contributor to the global diversity of RNA sequences in the human brain. A-to-I editing occurs either at an isolated adenosine (‘selective editing’) or across many neighboring adenosines in an extended region on the same transcript (‘hyper- editing’). These base-specific alterations occur across most neuronal and non-neuronal expressed genes, and are required for normal brain function. A-to-I editing has been shown to influence alternative splicing, recode amino acid sequences of proteins, alter the ability of miRNAs to bind to their target sites, and change the stability of RNA secondary structures. Moreover, recent work show that these modifications are tightly regulated in the brain, and changes in editing levels are tied to etiology of neurodevelopmental and neurodegenerative disorders, including Alzheimer’s disease (AD). Nevertheless, major gaps exist in understanding the neuropathological roles of A-to-I editing in the AD brain. The vast majority of sites are likely to be dynamically regulated among different cell types, brain regions in AD and across dementia severity. Yet, the status quo as it pertains to such context- dependent regulation of RNA editing can be summarized as little or none. Moreover, while most efforts have studied individual selective A-to-I editing sites independently, there is a complete dearth of research on the role of A-to-I hyper-editing and hyper-edited genes in AD, which have profound effects on transcriptional and translational regulation. Finally, while existing studies on the regulation of RNA editing mainly focused on the adenosine deaminase acting on RNA enzymes, the role of cis-acting genetic regulation (editing quantitative trait loci [edQTLs]) has been understudied and underpowered. This proposal will capitalize on the success of large- scale genomics and consortia efforts to elucidate functional and highly regulated RNA editing sites in normal aging and AD at a previously impossible scale. The current proposal is designed to overcome current knowledge gaps by: Aim 1) Addressing the unmet need for basic neuroscientific research that can capture fundamental regulation of RNA editing across multiple brain regions and cell types in normal aging and AD; Aim 2) Integrating individual genetic information from large cohorts to build powerful edQTL maps and uncover credible sets of AD risk loci that exert their pathogenic effects by changing RNA editing levels in the brain; Aim 3) Applying data- driven computational methods to annotate and prioritize functionally important RNA editing sites and hyper- edited genes strongly linked to AD, thereby advancing our understanding of the complex etiology of AD through the lens of RNA modifications. Results from this proposal will generate a more complete picture of the molecular and genetic landscape of AD, and will advance the identification of new therapeutic targets.