THESIS
2019
ix, 66 pages : illustrations (some color) ; 30 cm
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 t...[
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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.
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