The remarkably prevalent RNA editing and modifications (which constitute the epitranscriptome) contribute to transcriptome diversity and flexibility. One of the most common types is adenosine-to- inosine (A-to-I), catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes. ADAR binds to double-stranded RNA (dsRNA) and deaminates specific adenosine to inosine, which is read as guanosine by the cellular machinery. Loss of ADAR leads to a range of neurological phenotypes as demonstrated in model organisms. Alteration of RNA editing levels is associated with a number of neurological disorders. The regulation of RNA editing is very dynamic, varying in different tissues and at different developmental stages. While our previous work funded by this grant led to an unprecedented view of dynamic regulation at the tissue level, the measurements represent an average of many cells with widely variable or largely equal editing levels. We lack a good understanding of how much RNA editing varies between different cell types or even single cells. Particularly in the brain, where neurons are highly plastic and many cell types exist, RNA editing may play a role in fine-tuning mRNA messages that modulate brain function and neuronal connectivity throughout life. In this work, we aim to understand the dynamic regulation of RNA editing at an unprecedented depth. First, we will profile RNA editing in different neuronal cell types in flies, mice, and humans. We will also examine the changes of editing during developmental stages and in response to environmental stimuli in model organisms. Second, we will assign functions of RNA editing in different neural circuits in Drosophila using a highly automated and sensitive phenotypic assay. Finally, to mechanistically dissect the dynamic regulation, we will identify and validate additional RNA editing regulators and determine the mechanisms by which these regulators influence editing in Drosophila and mammals. This work will provide a deeper understanding of the dynamic regulation of A-to-I RNA editing in different neuronal cell types and shed light on the role of RNA editing in brain function.
RNA editing plays important functions in the brain and has been linked to human neurological diseases and other diseases; however, we have poorly understanding of its dynamic regulation in different neural circuits. We propose to systematically profile editing in different neuronal cell types and further dissect the mechanism of the dynamic regulation. Our work will provide a new perspective to understand human neurological disorders.
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