DOI
https://doi.org/10.25772/6YBE-TK23
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Nanoscience and Nanotechnology
First Advisor
Richard Inho Joh
Abstract
The centromere is crucial for chromosomal stability and their proper segregation during cell division in eukaryotes. Surrounding the centromere are pericentromeres, made of repetitive DNA elements called pericentromeric repeats, varying from 10 in fission yeast to thousands in humans. These repeats form densely packed heterochromatin, where genes are usually silenced. The silencing mechanism across different pericentromeric repeats remains unclear.
Despite variations in sequence and length, pericentromeric repeats are conserved across eukaryotes, indicating their functional importance. This dissertation presents mathematical models to quantify gene silencing in fission yeast and humans. In fission yeast, my model predicts that silencing occurs only with multiple copies of repeats. It also suggests that reducing repeat copy numbers can lead to desilencing, with factors like faster cell division and higher noise favoring this state.
Recent studies suggest that human satellite II repeats in cancer increase by the integration of RNA-derived cDNA by the process called reverse transcription. This dissertation explores the ODE-based and polymer chain models, which describe the dynamics of human satellite II (HSATII) repeats. Both models predict that reduced methylation leads to repeat number expansion. The ODE model also suggests the coexistence of high and low steady states of HSATII copy numbers, while the polymer chain model helps understand the spatial structure of repeats.
In conclusion, my study highlights the significant role of pericentromeric repeat copy numbers, a conserved chromosomal feature in eukaryotes. Future studies may reveal how different underlying silencing mechanisms contribute to various structures across species.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-8-2024
Included in
Biological and Chemical Physics Commons, Dynamic Systems Commons, Non-linear Dynamics Commons, Numerical Analysis and Computation Commons, Ordinary Differential Equations and Applied Dynamics Commons