Every human cell adds a chemical cap to its messenger RNA molecules to protect them from degradation, but this project reveals that different cell types assemble different capping machines to control which genes are expressed. The problem is that biologists have long assumed the mRNA capping process is identical in all cells. This research shows it is not. The enzymes that build the cap vary between tissues and change during cell differentiation, allowing cells to coordinate the expression of entire gene families as they take on new identities. Without understanding this regulation, we cannot explain how a single fertilised egg produces hundreds of distinct cell types. If the project succeeds, it will reveal the mechanisms that govern which genes get capped and expressed in a given cell. This is fundamental science—it does not aim to produce a drug or device. But a deeper grasp of how cells switch identities could eventually inform regenerative medicine, where controlling cell fate is essential, or cancer biology, where differentiation goes awry. Past discoveries in gene regulation have repeatedly opened unexpected routes to therapy.
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Human life utilises hundreds of cell types with massive diversity in function defined largely by which proteins they express. We will determine how regulation of the mRNA cap modification coordinates the gene expression required in different cell types. The cap protects mRNA from degradation and recruits processing and translation factors. The enzymes which catalyse cap formation were perceived as acting on all genes, in every cell. Our research reveals that the capping enzyme complexes are differentially expressed in different tissues and have gene-specific impacts. During cell differentiation, we demonstrate that changes in capping enzyme complexes result in coregulation of gene families, which we hypothesise co-ordinates the gene regulation required for new cell identities to emerge. Key goals are to determine: - mechanisms governing capping enzyme gene-specificity - how co-factors influence capping enzyme functionality - the impact of mRNA cap regulation in differentiation In pluripotent cells, the components of mRNA capping enzyme complexes will be characterised and their impact on enzyme kinetics, cap formation and sequence-specific RNA selection determined. During differentiation, how mRNA capping enzyme regulation impacts on enzyme function and gene expression will be investigated. This project will determine the dynamic impact of mRNA capping enzyme regulation. Keywords: gene regulation; mRNA; cell function
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