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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102484-01A1
Application #
8506659
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Krasnewich, Donna M
Project Start
2013-05-06
Project End
2018-04-30
Budget Start
2013-05-06
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$314,000
Indirect Cost
$114,000
Name
Stanford University
Department
Genetics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Walkley, Carl R; Li, Jin Billy (2017) Rewriting the transcriptome: adenosine-to-inosine RNA editing by ADARs. Genome Biol 18:205
Tan, Meng How; Li, Qin; Shanmugam, Raghuvaran et al. (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254
Yablonovitch, Arielle L; Fu, Jeremy; Li, Kexin et al. (2017) Regulation of gene expression and RNA editing in Drosophila adapting to divergent microclimates. Nat Commun 8:1570
Gal-Mark, Nurit; Shallev, Lea; Sweetat, Sahar et al. (2017) Abnormalities in A-to-I RNA editing patterns in CNS injuries correlate with dynamic changes in cell type composition. Sci Rep 7:43421
Zhang, Rui; Deng, Patricia; Jacobson, Dionna et al. (2017) Evolutionary analysis reveals regulatory and functional landscape of coding and non-coding RNA editing. PLoS Genet 13:e1006563
Ramaswami, Gokul; Li, Jin Billy (2016) Identification of human RNA editing sites: A historical perspective. Methods 107:42-7
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
George, Cyril X; Ramaswami, Gokul; Li, Jin Billy et al. (2016) Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses. J Biol Chem 291:6158-68
Ramaswami, Gokul; Deng, Patricia; Zhang, Rui et al. (2015) Genetic mapping uncovers cis-regulatory landscape of RNA editing. Nat Commun 6:8194
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 28:515-528

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