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Title: Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency
Author: Patani, Hemalvi
ISNI:       0000 0004 8503 9851
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Aberrant DNA hypermethylation of promoter CpG islands in the context of a hypomethylated genome is a hallmark of cancer. DNA hypomethylation is typically associated with genomic instability while CpG island hypermethylation is often linked to gene repression. The mechanisms underlying these changes and the role they play in cancer initiation and progression remain elusive as they are challenging to study once cancers have progressed, and no human experimental models exist to mechanistically investigate this phenomenon. We observed that upon reprogramming of primed human embryonic stem cells to the naïve state, the acquisition of a globally hypomethylated genome is accompanied by hypermethylation of bivalent promoter CpG islands, thus resembling DNA methylation patterns characteristic of the human cancer methylome. We dissected the kinetics of these DNA methylation changes at high temporal resolution. We found that a subset of bivalent genes which are enriched in developmental pathways become hypermethylated, and showed that this is mirrored across multiple cancers, suggesting common underlying mechanisms of DNA hypermethylation. To gain insight into the mechanism of hypermethylation, we investigated the dynamic expression of DNA methylation regulators upon reprogramming. We identified the de novo DNA methyltransferase DNMT3A as the enzyme primarily responsible for DNA hypermethylation, and characterised the consequences of its absence on the naïve pluripotent state. Additionally, we demonstrated a role of transcription factors and the pluripotency network in coordinating de novo methylation. In parallel, we explored the impact of reprogramming on the genomic stability of naïve hESCs and investigated a potential relationship between reprogramming and DNA mutations. We observed evidence of chromosomal instability upon reprogramming, though the mutation frequency appears to remain unchanged. The similarities between DNA methylation patterns acquired during reprogramming to naïve pluripotency and oncogenic transformation, as well as indications of genomic instability upon reprogramming suggest a wider utility for this reprogramming system in understanding cancer formation.
Supervisor: Not available Sponsor: Medical Research Council ; Greg Wolf Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine and Dentistry ; DNA hypermethylation ; genomic instability ; gene repression ; cancer initiation ; oncogenic transformation