Saudi Cultural Missions Theses & Dissertations
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Item Restricted Epigenetic Gene Regulation by the Type I Restriction Modification Systems(University of Leicester, 2024-04) Althari, Yasmeen; Oggioni, MarcoEpigenetic modifications mediated by type I restriction modification systems in prokaryotes have been linked to gene regulation. In Streptococcus pneumoniae, differential expression of alternative specificity subunits within the SpnIII type I restriction modification system had been shown to selectively modulate bacterial virulence. Given the presence of this system in the core genome of pneumococci, but not of the related Streptococcus mitis, SpnIII could represent a conserved phase-variable regulatory mechanism operating on a global scale. However, this phenomenon had yet to be examined at the single-gene level, and the underlying molecular mechanism remained unexplored. In this study, I utilised pneumococcal strains locked for alternative specificity subunits (no phase-variation at the locus) to validate methylation-dependent differential gene expression of several model genes using various transcriptomic and translation reporter assays. Additionally, I delved into the complexity of recombination within the spnIII locus, which is partially governed by a site-specific tyrosine recombinase whose mechanism of controlling the rate of recombination remains elusive. To investigate the regulation of this recombinase, I explored the possibility of its control by a hairpin structure in the 5-prime UTR of the gene representing a potential RNA thermosensor, considering the recognised temperature sensitivity of recombination. To provide evidence to support my hypothesis on epigenetic gene regulation, I analysed the non-phase variable prototype type I EcoKI system in Escherichia coli which revealed a similar methylation-dependent differential expression following deletion of the EcoKI methyltransferase. This discovery underscores the epigenetic impact of type I RMSs, suggesting a widespread occurrence and possibly a global relevance of this phenomenon across bacterial genera. Overall, my findings propose that methylation influences both local gene topology and global genome architecture, thus playing a crucial role in methylation-mediated regulation. This mechanism involves the interplay between methylation and DNA-binding proteins, which collectively shape the overall genome architecture and transcriptional landscape.12 0Item Restricted Investigating N3-methylcytosine Modification: Implications for Synaptic Regulation(Saudi Digital Library, 2023-11-24) Shaker, Hala; Knight, HelenThe present investigation focuses on the roles and locations of m3C RNA modifications in cellular systems, with a particular emphasis on their impact on neuronal plasticity. Historically, m3C modifications have been predominantly and narrowly attributed to mitochondrial tRNA. Such a limited perspective, however, undeniably raises fundamental questions, especially given the restricted understanding of m3C's broader distribution across diverse RNA categories. To address this significant lacuna in our knowledge, the current research embarks on a meticulous and exhaustive examination. This rigorous investigation revealed the surprising presence of m3C modifications not only in the expected tRNA but also across other RNA species. This ground-breaking discovery inherently challenges extant paradigms in the vast field of cellular RNA biology, mandating a thorough and comprehensive re-evaluation of previous assumptions. Utilising an analytical approach, the study explored the functional dimensions of highly m3C-modified transcripts. A comparative analysis was executed, differentiating their functionalities between the wild-type and the conditions subsequent to METTL8 deletion, thereby providing a dynamic picture of their behaviour specifically, in synaptic regulation. Furthermore, evaluations were conducted to assess the abundance of m3C modifications beyond the mitochondria under conditions of NMDA receptor activation. This approach provided a more nuanced, in-depth understanding of the findings, shedding light on previously uncharted territories. In the end, the research shows that m3C modifications may play essential roles in a wide range of cellular operations. Moreover, this study provided evidence indicating that the presence of m3C modifications extends beyond the mitochondria. Implications for future studies abound.23 0