Through the efforts of the Human Genome Project and other large-scale investigations, it has become clear that the molecular origins of human complexity, disease, and distinctness from other organisms are rooted in more than just the number of genes in the genome. RNA editing, the post-transcriptional alteration of genome-encoded information by chemical modification of individual RNA bases, provides a potentially powerful way to diversify the set of RNAs expressed in an organism's tissues over time. Aberrant RNA editing has been implicated in human neurological diseases such as amyotrophic lateral sclerosis, epilepsy, depression, suicide, glioma, and cancers, and may have contributed to the evolutionary development of human neurobiology and cognition. While numerous RNA editing sites have been identified to date, we are still far from possessing a complete list of RNA editing targets particularly in the coding regions, thus hindering a full understanding of the complexity of this process and its potential for therapeutic intervention. We propose to extend our recent success at developing experimental and computational frameworks to the generation of a comprehensive atlas of RNA editing sites in humans and mice. By combining multiple validated techniques, we will rigorously quantitate RNA editing in a spectrum of matched human and mouse tissues from multiple developmental stages. We will use this approach to extend our analysis to RNA editing in other primates such as chimpanzees and rhesus macaque monkeys, with the expectation of uncovering the contributions of RNA editing to conserved functions as well as to human-specific neural evolution. We will also carry out large-scale computational analysis to search for RNA editing-related functional elements in the annotated genomic and transcriptomic datasets. Finally, we propose to use a variety of mouse strains mutated for the enzymes that perform RNA editing to elucidate the regulation of RNA editing. Taken together, the goals of this proposed project will deepen our understanding of the molecular basis of RNA editing, generate a set of experimental and computational tools to drive innovation in the RNA editing field, and unravel the network of signals that regulate RNA editing spatiotemporally, thus bringing us closer to the goal of manipulating RNA editing to alleviate human disease.
RNA editing, which occurs when the message encoded by a DNA sequence is changed without accompanying changes in the DNA itself, has been associated with various human neurological diseases and cancers as well as with evolution of human cognition. We propose to apply cutting-edge experimental and computational techniques to uncover the full set of RNA editing sites in several mammalian genomes, including humans, and to unravel the functions and control of RNA editing in various tissues over time. This knowledge will provide a foundation for future manipulation of RNA editing to alleviate human diseases.
|Liddicoat, Brian J; Hartner, Jochen C; Piskol, Robert et al. (2016) Adenosine-to-inosine RNA editing by ADAR1 is essential for normal murine erythropoiesis. Exp Hematol 44:947-63|
|Ramaswami, Gokul; Li, Jin Billy (2016) Identification of human RNA editing sites: A historical perspective. Methods 107:42-7|
|Han, Leng; Diao, Lixia; Yu, Shuangxing et al. (2015) The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers. Cancer Cell 28:515-28|
|Liddicoat, Brian J; Piskol, Robert; Chalk, Alistair M et al. (2015) RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349:1115-20|
|Ramaswami, Gokul; Deng, Patricia; Zhang, Rui et al. (2015) Genetic mapping uncovers cis-regulatory landscape of RNA editing. Nat Commun 6:8194|
|Sapiro, Anne L; Deng, Patricia; Zhang, Rui et al. (2015) Cis regulatory effects on A-to-I RNA editing in related Drosophila species. Cell Rep 11:697-703|
|Bazak, Lily; Haviv, Ami; Barak, Michal et al. (2014) A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res 24:365-76|
|Ren, Xingjie; Yang, Zhihao; Xu, Jiang et al. (2014) Enhanced specificity and efficiency of the CRISPR/Cas9 system with optimized sgRNA parameters in Drosophila. Cell Rep 9:1151-62|
|Ramaswami, Gokul; Li, Jin Billy (2014) RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res 42:D109-13|
|Zhang, Rui; Li, Xin; Ramaswami, Gokul et al. (2014) Quantifying RNA allelic ratios by microfluidic multiplex PCR and sequencing. Nat Methods 11:51-4|
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