Multiscale nuclear mechanobiology within the skin: from biophysical cues to epigenetic effects

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The epidermis of the skin forms an essential physical barrier to the external environment, and it is continuously exposed to complex biomechanical forces. While it is well known that mechanical and biophysical cues regulate diverse cellular functions, such as growth, migration, and survival, the molecular level mechanisms by which cells within the skin sense these forces remains poorly understood. As the nucleus is the central organelle within which DNA is packaged and this internal structure defines specific patterns of gene expression, we hypothesise that the nucleus is a major mechano-sensing element within the cell: Mechanically induced changes in nuclear shape influence the internal structure and transcription of genes. Indeed, our preliminary data indicate that keratinocytes exposed to defined physical cues display changes in nuclear size and shape, and these changes in nuclear morphology correlate with altered DNA structure.The overall objective of the proposed project is to understand how forces are transmitted from the external environment to the nucleus and to determine the subsequent effects on nuclear structure, gene expression, and cell function within the epidermis of the skin. We will use advanced biophysical and imaging techniques to apply forces to single cells, and systems biology methodologies to analyse the changes in DNA structure and gene expression. In addition, we will test the role of internal cellular structures, such as the cytoskeleton, to gain mechanistic insight into these processes. Finally, we will investigate the influence of nuclear mechano-sensing in more complex 3D models of human skin.The successful completion of this project will provide fundamental and significant insights into how cells sense mechanical forces, in particular the role of the nucleus. This knowledge will advance our understanding of normal skin physiology and mechanical function. Additional impacts of the proposed project include the development of new biophysical tools and technologies, building new collaborations with academics and industry, and multi-disciplinary training for the scientists involved. Future studies following on from this work could involve investigation of additional aspects of nuclear structure and examining the role of these mechanotransduction pathways in skin diseases such as blistering, scarring, or cancer.