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Title: Role of plectin in nuclear mechano-transduction of keratinocytes
Author: Veiga de Macedo Almeida, Filipe
ISNI:       0000 0004 7962 4616
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2016
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Cell shape dictates nuclear morphology via cytoskeleton remodelling, potentially regulating therefore nuclear architecture and gene expression. Utilising micro-patterned substrates to control cell shape, the physical cell-nuclear integration was investigated. Cells were seeded in patterns with variable sizes and shapes, and the nuclear morphology assessed. The nucleus in spread cells was larger when compared with confined cells as measured by its volume. Actin and keratins are the two main determinants of keratinocytes mechanics and their role in defining nuclear morphology is still unclear. Results here showed that the inhibition of filamentous actin, therefore the formation of stress fibres, was not sufficient to disrupt the physical link between cell shape and nuclear morphology in keratinocytes. Plectin deficient keratinocytes were further investigated as they possess abnormal keratin architecture: their more open network of keratin 14 resulted in a larger and more deformable nucleus. These deformations depended on acto-myosin contractility and the formation of cell-cell contacts. When seeded as cell clusters with a confined adhesive area, Plec KO were able to compact to a higher extent and when allowed to migrate outside this confined area, the nucleus of Plec KO underwent larger and quicker morphological remodelling in comparison to the WT. Changes in nuclear morphology may influence chromatin remodelling. Confined keratinocytes committed to terminal differentiation, had lower levels of transcriptionally active sites (H3K4me3), and re-distributed heterochromatin markers (H3K27me3). In summary, the present thesis demonstrates that cell shape mediates nuclear morphology and chromatin remodelling, and this cell-nucleus coupling is coordinated by the cross-talk between keratins and actin, in which plectin is a key player.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Engineering and Materials Science ; Cell shape ; nuclear morphology