Actin cytoskeleton: Regulation through protein interactions and epigenetic re-programming

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The shape of each cell in the human body is determined by an internal structure called the cytoskeleton, which is a network of interconnected proteins that provides a "load-bearing" structure that enables movement and provides protection from potentially damaging external forces. Two of the most important cytoskeleton proteins are actin and myosin. Individual actin molecules can be joined together to form long fibres. Myosin is a large protein complex, composed of 2 heavy chains, 2 essential light chains and 2 regulatory light chains. Actin fibres and myosin complexes bind to each other, and when myosin is activated it pulls on the actin fibres they are bound to, shortening the length of actin-myosin fibres and leading to tension in the cytoskeleton network. Since the cytoskeleton is responsible for protecting cells from damaging external forces, it is important for cells to adjust the physical strength of their cytoskeleton to adapt to changing environments. An important way that cells reinforce their cytoskeleton is to activate the myosin complex to shrink the length of actin-myosin fibres. This actin-myosin fibre shortening produces cytoskeleton tension that makes cells physically stiffer. In addition to myosin activation, there may be changes in the collection of proteins that are associated with the cytoskeleton. In this proposal, we will identify the proteins that are part of the cytoskeleton when it is relaxed, and discover how the collection of associated proteins changes when the cytoskeleton becomes tense. If the environment undergoes long term changes in how it exerts pressure on cells, cells may compensate by rapidly changing how specific genes are expressed, and even by modifying their DNA to alter the long-term expression of genes that contribute to the cytoskeleton's physical strength. In this proposal, we will determine if cells "re-wire" their DNA to change gene expression patterns if cytoskeleton tension is prolonged, and we will identify the cytoskeleton-related genes that are expressed differently as a result of these DNA alterations. The experiments in this proposal will be the first to systematically examine how the complex of proteins in the cytoskeleton changes between the relaxed and contracted states, and how sustained cytoskeleton contraction alters the expression of genes encoding for proteins related to cytoskeleton organization and function. The proposed research will benefit Canadians by: 1) Leading to novel discoveries in cell biology and cytoskeleton regulation that will enhance Canada's scientific reputation and innovation potential; 2) Training of highly-qualified personnel to expand their career perspectives and increase future employability in academic or industrial biomedical research so that they may contribute to Canada's knowledge economy; 3) Development of novel multi-disciplinary approaches and generation of unique biological research tools that will be shared with the Canadian research community.