Actin-associated adhesion proteins as regulators of nuclear function

Cell function is profoundly influenced by the physical environment of the body. Changes in the stiffness of tissue environments are vital for organs to grow and wounds to heal. Cells detect and respond to such changes to adapt to mechanical strain, maintain tissue structure and coordinate cell movement. To do this, cells use their cytoskeleton to transmit mechanical force rapidly from their surroundings, via adhesion proteins at the cell surface, to the nucleus. At the nucleus, force is then converted to biochemical signals that trigger alterations in nuclear shape and rearrangements of DNA. These signals regulate processes that are fundamental to tissue growth and development, including cell movement and gene expression. Abnormal nuclear shape and altered mechanical properties are hallmarks of ageing and various diseases, highlighting the importance of understanding the processes underlying how cells respond to tissue stiffness. Remarkably little is known about how force actually leads to the precise gene expression changes required for cells to respond to their physical environment. A key challenge is the lack of detailed understanding of the molecular events that regulate this process at the nucleus. I will address this fundamental question by building on my recent unexpected discovery that some adhesion proteins, usually found near the cell surface, can locate in and around the nucleus to regulate gene expression. The surface of the nucleus is an essential interface point for registering force within the cell, so my aim is to investigate the role of adhesion proteins at the surface of the nucleus, and how they connect the cytoskeleton to the nucleus to regulate nuclear functions. I will focus on an adhesion protein called Mena, which is important for controlling how the cytoskeleton forms in cells. I found that Mena locates on the nuclear surface, where I predict it has a key role in regulating the linkage of the cytoskeleton to the nucleus. My objectives are: To establish how Mena regulates the cytoskeleton-to-nucleus connection to allow cells to respond to different physical factors, such as stiff surroundings and confined spaces, which can be encountered in different tissue environments. To determine how the association of Mena with the surface of the nucleus, and its connection to the cytoskeleton, alters DNA organisation to regulate the activity of genes. To identify how force influences a broader collection of cytoskeleton-associated adhesion proteins at the nuclear surface, and how they work with Mena to generate signals that control gene expression. This work will reveal how cells use adhesion proteins to regulate the transmission of force into the nucleus. This will impact our understanding of how fundamental nuclear functions are controlled as cells respond to the stiffness of their surroundings, and it will provide insight into the regulation of genes in tissue homeostasis, regeneration and therefore ageing. This research complements BBSRC’s mission to understand the rules of life, and closely aligns with its investment in bioscience for an integrated understanding of health. It will use sophisticated technologies to generate comprehensive maps of DNA function, and the molecular events that control this, that will be a valuable resource for the adhesion biology and gene regulation research communities. Importantly, the integration of these technologies with functional cell biology will build strategic skills capacity in data science and bioinformatics, UKRI priority areas, contributing to the development of a highly skilled workforce.