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

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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.