Transposable Element (TE) RNA regulation via small RNA pathways in aging cells and neurodegeneration.

项目总结/摘要 转座因子（Transposable elements，TE）是多产的遗传寄生物，其浸润>45%的人类基因组， 所有动物基因组的主要部分。衰老和疾病期间的TE激活会影响 神经元和改变动物活动。这一假设之所以有吸引力，是因为所有动物的基因组都含有一个主要的 动物幼年时处于潜伏状态，但在衰老和疾病期间被激活。我们 实验室研究了天然RNA干扰（RNAi）系统如何识别和沉默TE转录本， 保持基因组的稳定性。从根本上揭示动物基因组之间的调控机制 和神经退行性疾病的TE，我们正在部署遗传学，基因组学，生物化学和小RNA RNAi途径的分析方法。 这项提案将研究如何TE RNA在衰老过程中激活调节加工成小 RNA通过天然RNAi途径。这项研究利用了我们实验室以前建立的TE调查 调节在果蝇衰老过程中，我们将带来新的见解如何人类TE RNA也处理 以及这些TE小RNA水平在疾病状态下如何受到影响。的 最终的目标将是研究TE RNA调节如何在动物衰老过程中受到影响， 神经退行性疾病，如阿尔茨海默病、帕金森病和亨廷顿病。 本项目将实现以下目标：目标1：破译相关的染色质状态 在衰老的果蝇和人类细胞中TE表达升高;并测试基因干预， RNAi调控人类细胞和果蝇中的TE，并敲低和突变相关基因 为了测量对疾病表型抑制的反馈， 染色质状态。目的2：确定人脑组织发育和衰老过程中TE小RNA的分布范围; 并确定在神经退行性疾病中受影响的人脑TE小RNA的范围。以来 该领域仍然缺乏对动物衰老过程中TE RNA加工事件的完整理解，我们的多- 在果蝇模型系统中的一种prong遗传学和基因组学方法将补充翻译 目的是表征人类细胞和大脑样本中的TE RNA调控过程。

Project Summary/Abstract Transposable elements (TEs) are prolific genetic parasites infiltrating >45% of the human genome and are major proportions of all animal genomes. TE activation during aging and disease affects the transcriptomes of neurons and alter animal activity. This hypothesis is attractive because all animal genomes harbor a major reservoir of active TEs that are latent when animals are young but are activated during aging and disease. Our lab studies how the natural RNA interference (RNAi) system recognizes and silences TE transcripts to preserve genome stability. To fundamentally uncover the regulatory mechanisms between animal genomes and TEs in neurodegenerative disorders, we are deploying genetics, genomics, biochemical and small RNA analytical approaches on the RNAi pathway. This proposal will investigate how TE RNAs activated during aging are regulated by processing into small RNAs via natural RNAi pathways. This study leverages our lab’s previously established investigations of TE regulation during Drosophila aging, and we will bring new insight into how human TE RNAs are also processed into small RNAs during human aging and how these TE small RNA levels are affected in diseased states. The ultimate goal will be to examine how TE RNA regulation is affected during animal aging and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. This project will achieve the following aims in this project: Aim 1: Decipher the chromatin states associated with elevated TE expression in aging Drosophila and human cells; and test genetic interventions that modulate RNAi regulation of TEs in human cells and Drosophila with knockdowns and mutations of genes linked to neurodegeneration in order to measure the feedback to disease phenotype suppression and preserving chromatin states. Aim 2: Determine the range of human brain TE small RNAs during development and aging; and determine the range of human brain TE small RNAs being affected in neurodegenerative diseases. Since the field still lacks a complete understanding of TE RNA processing events during animal aging, our multi- prong genetic and genomics approach in the Drosophila model system will complement the translational objectives of characterizing the TE RNA regulation process in human cells and brain samples.