UCLA

It is well-established that RNA editing plays significant roles in brain function. Recent studies uncovered many RNA editing events with aberrant editing levels in neuropsychiatric and neurological diseases, such as Schizophrenia (SCZ) and Alzheimer’s disease (AD). Yet, the underlying mechanisms of dysregulation of these RNA editing abnormalities and their contribution to disease processes are generally unknown. In this dissertation, we carried out in-depth studies of RNA editing to gain an improved understanding of its implications in brain diseases. To better understand the roles of RNA editing in SCZ, we conducted global de novo RNA detection to probe editing differences between disease and control subjects in four independent SCZ cohorts. We observed reproducible and significantly reduced editing levels (i.e., hypoediting) in SCZ and an enrichment of dysregulated sites in genes involved in mitochondrial functions. Furthermore, we carried out experimental studies to characterize the functional roles of dysregulated RNA editing located in coding and non-coding regions. These studies again highlighted the important contributions of RNA editing to mitochondrial function. Next, we examined the relationship between genomic variation, RNA editing and other post-transcriptional processes in SCZ via quantitative trait loci (QTL) analyses. Detection of editing QTL (edQTL), splicing QTL (sQTL), and expression QTL (eQTL) in the CommonMind SCZ cohort revealed both common and distinct loci among the three types of QTL. In addition, we investigated each QTL-type in both European (EU) and African American (AA) populations, and observed that AA-specific QTL were associated with larger effect sizes. Finally, we demonstrated the disease relevance of QTL through their colocalization with the GWAS summary statistics of SCZ, bipolar disorder (BPD), and major depressive disorder (MDD), respectively. Recently, RNA editing was reported to significantly impact the immunogenicity of double-stranded RNAs (dsRNAs). Motivated by this relationship, we sought to examine dsRNA expression and RNA editing dysregulation in disease. To this end, we implemented a bioinformatic pipeline to predict dsRNA regions transcriptome-wide. Using RNA-seq data of AD patients and controls, we identified global upregulation of dsRNAs and downregulation of RNA editing in AD, a disorder for which emerging evidence supports the importance of inflammation and innate immunity in disease mechanisms. Interestingly, while differentially expressed dsRNAs and reduced RNA editing are observed in nonoverlapping loci, they both significantly associated with interferon (IFN) response. Our data suggest that reduced RNA editing and increased dsRNA expression collectively contribute to increased IFN response in AD, although through independent transcripts.