IPLS Seminar - Dr. John Connelly (Queen Mary University of London)

Abstract: The nucleus is a central force sensing element within the cell.  It is physically integrated with the cytoskeleton and supported by an internal nucleoskeleton, thereby enabling it to directly sense and adapt to external biophysical cues.  Importantly, force transmission to the nucleus can impact nuclear architecture, chromatin remodelling, and epigenetic gene regulation.  At the same time, a cell’s intrinsic epigenetic status can influence how it responds to extrinsic signals within the microenvironement. Our laboratory is interested in how the interplay between extracellular physical cues and epigenetic gene regulation controls cell fate and function within the epidermis of the skin.  We employ engineered in vitro models, such as micropatterned substrates, to manipulate the biophysical environment of human keratinocytes and investigate the downstream effects on nuclear architecture and gene expression using a combination of imaging and genomic methods. Our recent studies reveal that keratinocyte adhesion to the extracellular matrix regulates the size and shape of the nucleus, as well as the organisation of the nuclear lamina and the spatial distribution of heterchromatin.  In contrast, keratinocyte cell-cell adhesion acts as a buffer system and protects the nucleus from force-induced changes in chromatin remodelling. These mechanotransduction processes are mediated by dynamic cross-talk between the actin and keratin cytoskeletal networks, and play important functional roles in the regulation of keratinocyte terminal differentiation and migration.  Taken together, these studies have uncovered a complex network of regulatory mechanisms by which interactions between biophysical cues and chromatin remodelling control fundamental cellular processes that are essential for tissue homeostasis and repair.