The molecular underpinnings for specifying neuronal diversity and decline largely remain a mystery. One emerging idea is that the mobilization of transposons during aging and disease can disrupt the normal transcriptome profiles of individual neurons and alter animal activity. In both Drosophila and humans, the dominant transposon classes are retrotransposons which primarily mobilize via an RNA intermediate. Since RNA surveillance pathways, such as the RNAi-small RNA and Adar-RNA editing pathways, are key mechanisms implicated in transposon regulation, we hypothesize they also mediate neuronal diversity during development, but may decline during aging. To test this hypothesis, we will achieve the following aims in this project:
Aim 1 : Discover changing Transposon Landscapes (TLs) in Drosophila aging brains and neurons.
Aim 2 : Discover transcriptome and RNA editing changes in aged Drosophila brains and neurons that can be linked to changing TLs.
Aim 3 : Assess TLs and transcriptomes in brains with modulated RNA surveillance pathways. We will deeply sequence the genomes and transcriptomes from brains and highly purified neurons that regulate Drosophila activity. These data will allow us to integrate TL dynamics along with the diversification of RNA repertoires. Importantly, we will go beyond simple quantitative changes of coding mRNAs, because we will also discover novel RNA- editing events, lncRNAs, and small RNA populations. These transcriptome alterations may all converge on transposon regulation, so we will also examine if genetic modulation of RNAi/small RNA and Adar/RNA editing pathways can help neurons manage changing TLs and promote greater longevity and activity in aging animals.
This project will determine how Transposon Landscapes (TLs) change in aging neurons, and how these changes will influences RNA editing, gene expression and animal health. By using the highly tractable genetic model organism, Drosophila, we will quantify how TLs and transcriptomes change between young and aging Drosophila. We will then test genetic interventions of this phenomenon by overexpressing and reducing RNA surveillance pathways in Drosophila neurons, such as the RNA interference and editing enzymes. This study will reveal new pathways that can alleviate genetic damage to aging neurons.
|Clark, Josef P; Rahman, Reazur; Yang, Nachen et al. (2017) Drosophila PAF1 Modulates PIWI/piRNA Silencing Capacity. Curr Biol 27:2718-2726.e4|
|Toombs, James A; Sytnikova, Yuliya A; Chirn, Gung-Wei et al. (2017) Xenopus Piwi proteins interact with a broad proportion of the oocyte transcriptome. RNA 23:504-520|