Characterizing 3D epigenomes in pathological conditions

<p>The human genome is intricately folded within the confines of a minuscule nucleus, maintaining critical activities, including transcription, replication, and DNA repair. These processes are orchestrated by the epigenome. Prior research has established that both the epigenome and its three-dimensional structure are highly instructive to gene regulation, underscoring the importance of investigating the 3D epigenome under various cellular and disease conditions.</p> <p>In this dissertation, I perform an in-depth characterization of 3D epigenomes in two distinct pathological contexts: Trisomy 21 neural stem cells and cells acutely infected with SARS-CoV-2. For Trisomy 21 cells, I applied a cutting-edge, combinatorial indexing-based single-cell RNA sequencing approach to chart the developmental progression of trisomic brain organoids. This single-cell transcriptomic analysis uncovered impaired differentiation pathways in trisomic stem cells, leading to suboptimal development into neural progenitor cells and neurons. By employing chromatin conformation capture methodologies, I have detailed the 3D genome structures across different layers in Trisomy 21 neural stem cells.</p> <p>Turning to SARS-CoV-2, I charted the three-dimensional chromatin structure and comprehensive epigenomes during acute infection. My research reveals pronounced disruptions in host chromatin organization, highlighted by the weakening of compartment A, increased intermingling of compartments A and B, reduced interactions within topologically associating domains (TADs). Notably, a targeted depletion of the cohesin complex within TADs points to a potential interference with loop extrusion processes by the infection. Accompanying these structural and epigenome disturbances is the compromising of interferon-stimulated genes and an increase of proinflammatory genes, paralleling a rise in H3K4me3 modifications at the promoters of pro-inflammatory genes. This investigation not only characterizes the impact of SARS-CoV-2 acute infection on host chromatin but also lays the groundwork for future work into the long-lasting epigenomic consequences of infection.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Wang, Ruoyu
• <p>0000-0002-3644-1284</p>

Contributors dc:contributor

• Wenbo Li
• Francesca Cole
• Jichao Chen

• 3D genome
• epigenetics
• gene regulation
• Genomics
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1317

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2374