NETS coordinate genome organisation and gene expression changes in t-cells and during myogenesis
Robson, Michael Ian
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Gene positioning changes with respect to the nuclear periphery correlate with their activation in a number of tissues during development. However, the determination of the function this serves or the mechanism through which this was achieved has been remarkably difficult to resolve. It may now be possible to address these questions due to the recent identification of a number of tissue-specific nuclear envelope transmembrane proteins (NETs) which are capable of promoting the repositioning of specific subsets of chromosomes and concomitantly inducing changes to gene expression (Zuleger et al,. 2013). In this thesis I describe the role of NETs in the positioning of genes to the nuclear envelope (NE) during muscle differentiation and the role this activity plays in the optimisation of myogenic gene expression in as myoblasts (MTs) differentiate to myotubes (MTs). To do this I identified four NETs with the capacity to reposition a chromosome to the periphery that are present specifically in the NEs of skeletal muscle. Using a combination of genome-wide gene expression analysis and DamID I determined that depletion of these NETs disrupted myogenic gene expression and, more significantly, prevented the targeting to and silencing of normally repressed genes at the NE. I also investigated an analogous role for the blood-specific NET TAPBPL in the regulation of the critical T-cell regulator interleukin 2 (IL-2) at the NE in T-cells. Depletion of this NET caused release of the IL2 locus from the periphery and promoted its inappropriate and long-term activation. Interestingly, depletion of TAPBPL also prevented IL2 silencing following the end of T-cell activation, suggesting this genome organisation activity is critical for the maintenance of normal T-cell function. Collectively, the results discussed herein describe a new role for NETs in the regulation of gene expression through the manipulation of spatial genome organisation and may serve as an additional layer of higher order tissue-specific gene regulation in higher organisms.