Integrative epigenomic analyses of glial cells in brain disorders

Abstract

Although much of the human genome is non-coding, recent studies have demonstrated its important regulatory roles over the coding regions. Within this non-coding compartment, 46% are transposable elements (TEs), the majority of which are retrotransposons. These elements are mobile stretches of DNA that can move around the genome via a ‘copy-and-paste’ mechanism. Interestingly, retrotransposons possess cis-regulatory properties that can wield influence over host transcription. Moreover, recent studies have reported their aberrant expression in brain diseases. This study aims to delineate the cis-regulatory elements of the brain, with a particular focus on retrotransposons, in devastating and currently incurable diseases such as Alzheimer’s disease (AD) and glioblastoma (GBM). In the first objective, I analyzed an AD mouse model containing the human mutant APP transgene (R1.40) by transcriptomic profiling of four brain regions. In the second phase, I conducted a pilot study on a GBM sample by comparing its epigenomic landscape to publicly available datasets. Furthermore, to obtain oligodendrocyte- and neuron-specific epigenomic maps from frozen tissue, I developed and optimized protocols for fluorescence-activated nuclei sorting (FANS) and low cell input chromatin immunoprecipitation. The results indicate an inherent role for retrotransposons in the mouse brain, which is dysregulated in AD. Such retroelements also show global changes in H3K27ac enrichment in GBM. Taken together, these findings highlight an unappreciated role of repetitive elements in serious brain disorders and may shed light on their underlying molecular mechanisms.

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology