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Title: Investigating the transcriptional control of Dnmt3L and post-transcriptional control of Dnmt1
Author: Rutledge, Charlotte Emily
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2011
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In this thesis I present an investigation into mechanisms which regulate the expression of the DNA methyltransferase family members DNMT3L (a co-factor for de novo methylation) and DNMTl (the maintenance methyltransferase). I present work demonstrating the involvement of DNA methylation in the regulation of expression of DNMT3L from one of its three promoters, and also show that DNMT3L itself is required for this methylation to occur in murine oocytes. Furthermore, the data demonstrates that DNMT3L is required not only for DNA methylation of imprinted sequences in murine oocytes, as was previously hypothesised, but also for methylation of several non-imprinted single-copy and repeat sequences which were investigated, and that loss of this methylation in the oocyte results in altered gene expression. These altered patterns of expression have the potential to be maintained throughout early development. In separate work, experiments were conducted to investigate the role of RNA-binding proteins in the translational regulation of DNMTl. Highly conserved consensus binding motifs for several RNA-binding proteins are located in the 3'UTR of DNMT1. Work conducted in human cell lines and murine embryonic stem cells indicates a role for ePEB, MSIl and PUM2 (proteins which are reported to function predominantly via regulation of mRNA polyadenylation) in the positive translational regulation of DNMTl. A thorough investigation of cell cycle-dependent polyadenylation changes for the DNMTl mRNA failed to reveal such regulation, despite evidence of polyadenylation at control mRNAs. These experiments further our understanding of the mechanisms which are involved in the correct regulation of the expression of these important epigenetic regulators, dysregulation of which may result in human diseases which incorporate epigenetic alterations, such as imprinting syndromes and cancers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available