Untangling sources of DNA methylation variability in the context of development and rare diseases
department or school: Science, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Fu, Maggie Po Yuan
issued: 2025-10-20T21:09:58Z
issued: 2025
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Epigenetic marks are essential for maintaining cellular identity and functions, through regulation of chromatin structure and transcriptional activation. This process is especially relevant in early development during cell differentiation, where chromatin organization and DNA methylation (DNAme) patterns serve as âepigenetic barriersâ to preserve cellular identity. Disruptions in epigenetic regulation are therefore commonly associated with atypical development. Yet, the direct mechanisms underlying the role of epigenetic dysregulation in pathology remain an area of active research. One challenge in the field of research originates from the plasticity of DNAme; specifically, as DNAme can be modified by factors including cellular identity, biological sex, age, and environmental factors, it can be difficult to tease apart the signals driving its variability. The overarching objective of my thesis is to develop bioinformatic tools to better dissect the sources of DNAme variability, with a focus on rare diseases of epigenetic origin. Chapter 2 describes a patient with compound heterozygous variants in ASXL1, combined immunodeficiency, and EBV-associated B-cell lymphoma. I reported an altered DNAme landscape and associated immune cell dysfunction associated with the patientâs clinical phenotypes. In Chapter 3, I curated population-specific reference DNAme datasets to enable detection of disease-associated DNAme signatures, comparing multiple statistical methods. Chapter 4 details the optimization of a cell type prediction pipeline for pediatric samples using machine learning, alongside the development of a user-friendly R package that empowers future research in pediatric and longitudinal immune dynamics. Finally, in Chapter 5, I synthesized current strategies for addressing cellular heterogeneity in DNAme analyses and proposed a set of best-practice guidelines. Together, this body of work supports more accurate identification of DNAme patterns associated with rare diseas…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/92678
note: UNTANGLING SOURCES OF DNA METHYLATION VARIABILITY IN THE CONTEXT OF DEVELOPMENT AND RARE DISEASES by Maggie Po Yuan Fu B.Sc, The University of British Columbia, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Genome Science and Technology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2025 © Maggie Po Yuan Fu, 2025ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: UNTANGLING SOURCES OF DNA METHYLATION VARIABILITY IN THE CONTEXT OF DEVELOPMENT AND RARE DISEASES submitted by Maggie Po Yuan Fu in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Genome Science and Technology Examining Committee: Dr. Michael S. Kobor, Professor, Medical Genetics, UBC Supervisor Dr. Eldon Emberly, Professor, Physics, Simon Fraser University Supervisory Committee Member Dr. Wan L. Lam, Professor, Pathology and Laboratory Medicine, UBC University Examiner Dr. Christian G. Steidl, Professor, Pathology and Laboratory Medicine, UBC University Examiner Additional Supervisory Committee Members: Dr. Keegan Korthsauer, Assistant Professor, Statistics, UBC Supervisory Committee Member Dr. William T. Gibson, Professor, Medical Genetics, UBC Supervisory Committee Member iii Abstract Epigenetic marks are essential for maintaining cellular identity and functions, through regulation of chromatin structure and transcriptional activation. This process is especially relevant in early development during cell differentiation, where chromatin organization and DNA methylation (DNAme) patterns serve as âepigenetic barriersâ to preserve cellular identity. Disruptions in epigenetic regulation are therefore commonly associated with atypical development. Yet, the direct mechanisms underlying the role of epigenetic dysregulation in pathology remain an…
has type: Thesis/Dissertation
date issued: 2025-11
is shown at: 10.14288/1.0450498
language: eng
degree discipline: Genome Science and Technology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Kobor, Michael S. (Geneticist)
type: Text
identifier URI: http://hdl.handle.net/2429/92678