Transposon landscapes and transcriptome diversity in aging neurons

 描述(由申请人提供)：确定神经元多样性和衰退的分子基础在很大程度上仍然是一个谜。一个新兴的想法是，在衰老和疾病期间转座子的动员可以扰乱单个神经元的正常转录组特征，并改变动物的活动。在果蝇和人类中，占主导地位的转座子类别是反转录转座子，它主要通过RNA中间体来动员。由于RNA监视通路，如RNAi-Small RNA和Adar-RNA编辑通路，是转座子调控的关键机制，我们假设它们也在发育过程中调节神经元多样性，但可能随着年龄的增长而下降。为了验证这一假设，我们将在这个项目中实现以下目标：目标1：在果蝇老化的大脑和神经元中发现不断变化的转座子景观(TL)。目的2：发现老年果蝇大脑和神经元中转录组和RNA编辑的变化，这可能与TL的变化有关。目的3：用调节的RNA监测通路评估大脑中的TL和转录本。我们将对调节果蝇活动的大脑和高纯度神经元的基因组和转录本进行深度测序。这些数据将使我们能够将TL的动态与RNA谱系的多样化结合起来。重要的是，我们将超越编码mRNAs的简单量化变化，因为我们还将发现新的RNA编辑事件、lncRNAs和小RNA群体。这些转录组的改变可能都集中在转座子的调控上，所以我们还将研究RNAi/小RNA和Adar/RNA编辑途径的遗传调制是否可以帮助神经元管理不断变化的TL，并促进老龄动物更长的寿命和活动。

 DESCRIPTION (provided by applicant): 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.