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Type of Resource (primo): dissertations
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Corporate
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Note: thesis: Thesis (Sc. M.)--Brown University, 2025
Genre (aat): theses
Abstract: Motivation: Many higher-order organisms display sexually dimorphic traits, specifically, sex-biased lifespan and aging phenotypes. There are several potential explanations for these phenomena––one of which involves the complex interplay between genes, transcription factors, and epigenetic markers to regulate various cellular and biological processes. Due to the complexity of the brain, sex-biased aging remains poorly understood, especially at the neural level. Objective: Within this thesis, I had two primary objectives––To characterize sex-biased alternative splice isoforms of synaptic genes across two major Drosophila melanogaster developmental stages, and determine whether the temporally coordinated pattern of synaptic gene expression and chromatin accessibility observed across D. melanogaster and M. musculus (mouse) CNS development is evolutionarily conserved in human brain-derived cells. Methods: For my first objective, I performed bulk RNA-sequencing analysis and transcriptome alignment on wild-type third instar and adult, male and female Drosophila. Next, I identified high-matching human orthologs of several synaptic genes that appear to be coordinately-regulated across both Drosophila and mouse development, and then analyzed time-series scRNA-seq and scATAC-seq data of roughly 650,000 human-derived cells. Results: I identified differential alternative splicing of genes associated with synaptic development and differentially enriched gene ontology pathways between biological sexes and across two major developmental stages. Separately, I found similar patterns of synaptic gene expression observed in flies and mice in several human cerebral organoids, but a unique pattern of chromatin accessibility only present in human cells. Conclusions: While there appear to be clear sex-biased splicing differences between biological sexes in D. melanogaster at the bulk level, future studies should expand splicing analysis across the entire continuum of Drosophila development, as well as integrate single-cell multiomics. Interestingly, chromatin accessibility appeared to oppose synaptic gene expression across developmental stages in human cells, suggesting a potential unique mechanism of transcription factor binding and subsequent remodeling of 3D genomic architecture during human development––one that should be investigated using paired multi omics integration. A future study that I have outlined and obtained preliminary results for will characterize the functional consequences of knocking down onecut, a candidate transcriptional regulator of synaptic development in Drosophila, through in-vivo analysis of the third instar larval neuromuscular junction.
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Subject
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Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01141063")
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