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

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.